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Controlling Dynamic DNA Reactions at the Surface of Single-Walled Carbon Nanotube Electrodes to Design Hybridization Platforms with a Specific Amperometric Readout
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Controlling Dynamic DNA Reactions at the Surface of Single-Walled Carbon Nanotube Electrodes to Design Hybridization Platforms with a Specific Amperometric Readout
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  • Simone Fortunati
    Simone Fortunati
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
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  • Ilaria Vasini
    Ilaria Vasini
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
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  • Marco Giannetto
    Marco Giannetto
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
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    Orcidhttps://orcid.org/0000-0001-7031-7466
  • Monica Mattarozzi
    Monica Mattarozzi
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
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  • Alessandro Porchetta
    Alessandro Porchetta
    Department of Chemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
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    Orcidhttps://orcid.org/0000-0002-4061-5574
  • Alessandro Bertucci*
    Alessandro Bertucci
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
    *E-mail: [email protected]
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    Orcidhttps://orcid.org/0000-0003-4842-9909
  • Maria Careri
    Maria Careri
    Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
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Analytical Chemistry

Cite this: Anal. Chem. 2022, 94, 12, 5075–5083
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https://doi.org/10.1021/acs.analchem.1c05294
Published March 18, 2022

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Abstract

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Carbon nanotube (CNT)-based electrodes are cheap, highly performing, and robust platforms for the fabrication of electrochemical sensors. Engineering programmable DNA nanotechnologies on the CNT surface can support the construction of new electrochemical DNA sensors providing an amperometric output in response to biomolecular recognition. This is a significant challenge, since it requires gaining control of specific hybridization processes and functional DNA systems at the interface, while limiting DNA physisorption on the electrode surface, which contributes to nonspecific signal. In this study, we provide design rules to program dynamic DNA structures at the surface of single-walled carbon nanotubes electrodes, showing that specific DNA interactions can be monitored through measurement of the current signal provided by redox-tagged DNA strands. We propose the use of pyrene as a backfilling agent to reduce nonspecific adsorption of reporter DNA strands and demonstrate the controlled formation of DNA duplexes on the electrode surface, which we then apply in the design and conduction of programmable DNA strand displacement reactions. Expanding on this aspect, we report the development of novel amperometric hybridization platforms based on artificial DNA structures templated by the small molecule melamine. These platforms enable dynamic strand exchange reactions orthogonal to conventional toehold-mediated strand displacement and may support new strategies in electrochemical sensing of biomolecular targets, combining the physicochemical properties of nanostructured carbon-based materials with programmable nucleic acid hybridization.

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Introduction

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Electrochemical sensors that use specific sequences of synthetic DNA as molecular receptors and DNA-based systems for signal generation and amplification enable the rapid detection of target molecules by converting programmable hybridization and specific biomolecular recognition into measurable electrical outputs. (1,2) Electrochemical DNA sensors harnessing redox-tagged DNA probes (E-DNA) anchored to gold electrodes have been engineered into point-of-care diagnostic devices enabling rapid, reagentless, amperometric detection of clinically relevant small molecules, nucleic acids, and proteins. (3−6) Strategies borrowed from DNA nanotechnology based on dynamic DNA structures and programmable reactions have bolstered a wide diversity in DNA recognition interfaces with improved sensitivity and specificity. (7−16) A precise control of the physicochemical properties and of the biomolecular recognition processes at the DNA–electrode interface is key to robust and efficient E-DNA platforms. This includes an optimization of the immobilization protocols, a control of the probe density and orientation, a minimization of unwanted nonspecific adsorption on the electrode surface, and a rational design of the molecular architecture. (17−20) Carbon nanotube screen-printed electrodes (CNT-SPEs) are a promising electrochemical platform because of their reduced cost compared with more widely used gold electrodes, their enhanced amplification of electrochemical signals based on their high conductivity, their large surface area that can accommodate an increased number of bioreceptors and their intrinsic electrocatalytic properties promoting electron transfer processes at the interface. (21−24) CNT surfaces give stable π–π interactions with the nucleobases of nucleic acids, which has been harnessed to produce biosensors that leverage noncovalent adsorption and target-induced desorption to generate electrochemical outputs. (25−28) However, sensing strategies built on this approach suffer from difficulties in achieving homogeneous and reproducible interfaces based on nonspecific π–π interactions and are limited to adsorption/desorption processes that do not allow engineering of more complex and dynamic molecular mechanisms. Alternatively, covalent surface functionalization with DNA probes enabled the design of electrochemical hybridization platforms in which molecular processes at the interface were monitored through label-free impedance measurements or voltammetric strategies based on the electrooxidation of nucleobases or intercalators. (29−34) Current formats of these sensors, though, measure changes in electrochemical properties at the interface rather than transduce sequence-specific molecular recognition events, and therefore, they do not allow monitoring of dynamic DNA reactions such as strand exchange processes. The strong noncovalent interactions between nucleic acids and carbon nanotubes also pose a substantial challenge in the design of E-DNAs based on CNT-SPEs, which requires an analysis of the extent to which nonspecific signal can extra-contribute to the expected target-induced amperometric output. Recently, Fortunati et al. and Liu et al. showed that dynamic nucleic acid systems and higher-order hybridization reactions can be interfaced with CNT-SPEs to develop amperometric biosensors in which the resulting current signal is ultimately generated through multistep, reagent-intensive, enzymatic processes. (35,36) To the best of our knowledge, CNT-SPE-based E-DNAs that allow direct amperometric monitoring of specific nucleic acid hybridization events have not been reported yet. In this context, we provide here design rules to program and control dynamic DNA structures at the surface of single-walled carbon nanotube screen-printed electrodes (SWCNT-SPEs) that enable direct amperometric monitoring of hybridization processes. We show how to reduce unwanted nonspecific interactions, demonstrate conduction and detection of programmable DNA strand displacement reactions, and then extend our approach to the formation and manipulation of recently discovered noncanonical DNA structures that can be used in the design of novel amperometric hybridization platforms.

Materials and Methods

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Trizma base, sodium hydroxide (NaOH), hydrochloric acid (37% w/v; HCl), acetic acid, dimethyl sulfoxide (DMSO), magnesium acetate tetrahydrate, magnesium chloride (MgCl2), N-(3-dimethyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS), sodium bicarbonate (NaHCO3), sodium dodecyl sulfate (SDS), ethylendiaminetetraacetic acid disodium salt dihydrate (EDTA), 4-morpholineethanesulfonic acid monohydrate (MES), pyrene, melamine, streptavidin–alkaline phosphatase from Streptomyces avidinii (ALP-Strp), Tween 20, and bovine serum albumin (BSA) were purchased from Merck (Milan, Italy). Hydroquinone diphosphate (HQDP) and single-walled, carbon nanotube screen-printed electrodes (DropSens DRP-110SWCNT) were purchased from Metrohm Italiana s.r.l. (Origgio, Italy). Synthetic DNA oligonucleotides, including biotinylated, amine-modified, Atto-MB2-modified, and Cy3-modified oligonucleotides, were purchased from Metabion (Germany).

Electrochemical Measurements

Voltammograms were acquired using a Metrohm Autolab PGSTAT204 equipped with NOVA 2.1.4 software and DRP-DSC boxed connector for SPE, purchased from Metrohm Italiana s.r.l. (Origgio, Italy). Amperometric signal of Atto-MB-2, which derives from the dye methylene blue, was measured by applying a preconditioning potential of −0.6 V for 30 s, followed by differential pulse voltammetry (DPV) analysis performed from −0.6 to 0 V. Hydroquinone amperometric signal was acquired applying a preconditioning potential of −0.5 V for 30 s, followed by DPV analysis performed from −0.5 V to +0.3 V. DPV acquisition parameters for analysis of both redox species were set as follows: step potential = +0.005 V; modulation amplitude = +0.05 V; modulation time = 0.1 s; interval time = 0.4 s. The DPV voltammograms were elaborated using the baseline correction function of NOVA 2.1.4, applying a polynomial algorithm for the determination of current peaks in the nanoampere range.

Data Treatment

The linear range, limit of detection (LOD), and limit of quantitation (LOQ) were calculated according to “Eurachem Guidelines”, (37) performing at least three replicated measurements for each concentration level.

Buffers

TAE buffer: 40 mM Trizma Base, 20 mM acetic acid, 2 mM EDTA, 12.5 mM magnesium acetate; pH was adjusted to 8.0 using 1 M HCl. TRIS buffer saline (TBS): 0.1 M Trizma base, 0.02 M MgCl2; pH was adjusted to 7.4 using 1 M HCl. TRIS buffer saline–Tween (TBS-T): 0.1 M Trizma Base, 0.02 M MgCl2, 0.05% w/v Tween 20; pH was adjusted to 7.4 using 1 M HCl. Carbonate buffer (CB): 0.1 M NaHCO3, 0.1% w/v SDS; pH was adjusted to 9.0 using 1 M NaOH. Reading buffer (RB): 0.1 M Trizma base, 0.02 M MgCl2; pH was adjusted to 9.8 using 0.1 M HCl. MES buffer: 0.1 M MES; pH was adjusted to 5.0 using 1 M NaOH.

Electrode Functionalization

SWCNT-SPEs were reacted with 50 μL of a 0.2 M EDC and 0.05 M NHS solution in MES buffer. After 30 min the electrodes were thoroughly rinsed with distilled water. Covalent immobilization of capture oligos was carried out incubating the NHS-functionalized electrodes with 50 μL of a 500 nM solution of amine-modified DNA probes in CB for 2 h, followed by washing with distilled water. Backfilling with pyrene was obtained by depositing on the SPE surface 50 μL of a 500 nM solution of pyrene in DMSO for 1 h, followed by washing with DMSO and distilled water.

Analysis of Surface Functionalization

Functionalization of SWCNT-SPEs was performed using a biotinylated DNA probe. Enzymatic labeling was then carried out through incubation for 15 min with a 10 ng/mL solution of ALP-Strp conjugate containing 20 mg/mL BSA in TBS buffer, followed by washing with TBS-T (1×) and TBS (1×). The amperometric readout was performed by depositing 50 μL of a 1 mg/mL solution of HQDP in reading buffer on the electrode surface for 150 s prior to DPV analysis. Probe density was estimated by performing functionalization of the electrode surface using Cy3-labeled, amine-modified DNA oligonucleotides and measuring the intensity of fluorescence emission of the Cy3 label in solution (λex = 540 nm, λem = 565 nm) on the FluoroMax-3 spectrofluorimeter (HORIBA JobinYvon, Bensheim, Germany).

DNA Hybridization Studies

Solutions of different concentrations (30, 50, 70, 100, 300, and 500 nM) of Atto-MB2-modified poly(A) DNA strands were prepared in TAE buffer, of which 50 μL were deposited on SWCNT-SPEs previously functionalized with amine-modified poly(T) probes and left incubating for 2 h. Next, the electrode surface was washed with TAE buffer and amperometric measurements were carried out in reading buffer. Control experiments for the evaluation of nonspecific amperometric signal due to DNA physisorption were conducted using a 100 nM solution of noncomplementary Atto-MB2-modified poly(T) strands.

Toehold-Mediated Strand Displacement Reactions

SWCNT-SPEs functionalized with 15-nt poly(T) DNA probes were reacted with a 100 nM solution of a complementary Atto-MB2-modified poly(A) sequence flanked by a 6-nt-long toehold domain (the full sequences are reported in Section 1 in the Supporting Information) in TAE buffer for 2 h, after which washing with TAE buffer was carried out. Next, strand displacement reactions were performed by incubating the electrode surface for 1 h with 50 μL of different concentrations (50 and 100 nM) of a sequence full complementary to the toehold-bearing strand of the surface duplexes. After washing with TAE buffer, amperometric measurements were conducted in reading buffer. Sequence-specificity experiments were conducted using solutions of invader probes (100 nM) bearing either one or three noncomplementary nucleobases in the toehold region, as well as a completely random sequence. Control experiments for the evaluation of nonspecific amperometric signal due to DNA physisorption were conducted by incubating SWCNT-SPEs functionalized with 15-nt poly(T) DNA probes with corresponding concentrations (50 and 100 nM) of a noncomplementary Atto-MB2-modified poly(T) strand.

Formation of Poly(T)-Melamine Duplexes on the Electrode Surface

SWCNT-SPEs functionalized with poly(T) DNA probes conjugated with 0, 3, or 6 GC bases were first incubated for 1 h with 25 μL of 200 nM solutions in TAE buffer of the complementary Atto-MB2-modified 15-nt poly(T) sequence (0GC), 15-nt poly(T) sequence conjugated with 3 G/C bases (3GC), or 15-nt poly(T) sequence conjugated with 6 G/C bases (6GC), respectively (see Figure 5b). Next, 25 μL of a 2 mM solution of melamine in TAE were added to a final volume of 50 μL of solution (1 mM melamine, 100 nM of 0GC, 3GC, or 6GC DNA strand, respectively) on the electrode surface, which was left incubating for another 1 h. Washing with TAE buffer was then carried out and amperometric measurements were conducted in reading buffer. In parallel, analogous experiments were carried out without addition of melamine.

Strand Exchange Reactions Based on Poly(T)-melamine Duplexes

SWCNT-SPEs functionalized with poly(T)-melamine duplexes, assembled using 15(T)-3GC-duplex-forming strands, were incubated for 1 h with 50 μL of a 100 nM solution of a 15-nt poly(A) sequence in TAE buffer. After washing with TAE buffer, amperometric measurements were conducted in reading buffer. Control experiments were conducted by repeating the same experimental steps without addition of melamine.

Results and Discussion

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Functionalization of SWCNT-SPEs with DNA Probes

Functionalization of SWCNT-SPEs with DNA probes through formation of covalent bonds can be obtained through a coupling reaction between the carboxylic acid groups present on the CNT surface and amine-modified oligonucleotides. Electrode surface treatment with EDC and NHS allows for the conversion of carboxylic groups into reactive NHS esters which can efficiently react with a terminal amine group on DNA probes to form stable amide bonds (Figure 1a). We used different concentrations of a 15-mer DNA oligonucleotide (capture probe) conjugated at the 5′-end with an amine group and at 3′-end with biotin (full sequences are reported in Section 1 in the Supporting Information) to modify SWCNT-SPEs and determine the concentration of DNA reactant in order to maximize surface functionalization.

Figure 1

Figure 1. (a) Schematic illustration of the functionalization of SWCNT-SPEs with amine-modified DNA probes. (b) Current signals obtained using different concentrations of biotinylated DNA probe reactant (mean value ± sd, n = 3, **p < 0.01, ns = nonsignificant) following incubation with alkaline phosphatase–streptavidin conjugates and its enzymatic substrate.

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The presence of a biotin molecule at the free 3′-end of the attached oligonucleotides allows for creating a complex with a streptavidin-alkaline phosphatase conjugate, thus, generating an amplified current signal by incubation with HQDP that is converted by the enzyme into electroactive hydroquinone. This is proportional to the amount of DNA probes attached to the electrode surface (Figure S1). As shown in Figure 1b, when a 500 nM concentration of amine-modified DNA oligonucleotides was used for the covalent modification of the electrodes, the resulting current signal was not statistically different (p > 0.05) from that obtained using a 5 μM concentration of the same oligos, indicating that a 500 nM concentration of amine-modified DNA reactant is sufficient to maximize the functionalization of SWCNT-SPEs with the desired DNA probes. Probe density expressed as the amount of DNA molecules attached per mm2 of electrode surface area was quantified by fluorescence spectroscopy and resulted to be approximately 4.3 × 1011 DNA probes/mm2, which is higher than the average values reported in the literature for DNA–gold electrode interfaces (Figure S2). (8,38)

Control of Nonspecific DNA Physisorption on the Electrode Surface

We then set out to determine the best experimental conditions for the control of specific hybridization processes at the interface. For this purpose, we investigated how to minimize nonspecific physisorption of DNA strands when a sample is left incubating on the CNT electrode, which is a dominant effect when single-stranded DNA is allowed to interact with carbon-based structures. (39) Our research group recently reported the use of pyrene as a backfilling agent to create a highly hydrophobic layer that is capable of greatly reducing the uncontrolled adsorption of peptide nucleic acid (PNA)-based probes, measured via an enzyme-based amplification process releasing an electroactive species in the working solution. (35) In the present work, we decided to study the efficiency of this backfilling strategy in the reduction of nonspecific physisorption of DNA-based probes labeled with a redox tag, which supports direct amperometric monitoring of hybridization events. Specifically, we used a model 15-mer DNA oligonucleotide not complementary to the surface DNA probes and conjugated with the Atto-MB2 redox tag to estimate how much of the amperometric signal attributable to nonspecific adsorption of the sample DNA at different concentrations can be reduced by a treatment of pristine SWCNT-SPEs with a pyrene solution in DMSO compared to the signal obtained without backfilling strategies (Figure 2a).

Figure 2

Figure 2. (a) Schematic illustration of the electrode surface treatment with pyrene as a backfilling agent to reduce nonspecific adsorption of DNA strands. MB is the Atto-MB2 redox tag. (b) Nonspecific signal reduction % relative to untreated electrodes when pyrene is used as a backfilling agent at different concentrations of a sample nonspecific DNA strand (mean value ± sd, n = 3). (c) Representative voltammograms obtained when redox-tagged nonspecific DNA (100 nM) was incubated on untreated (black curve), BSA-treated (blue curve) and pyrene-treated DNA-functionalized SWCNT-SPEs (red curve), and (d) the corresponding measured current signals (mean value ± sd, n = 3).

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As shown in (Figures 2b, S3 and S4), the use of pyrene as a backfilling agent determined a significant reduction of the amperometric output over the whole DNA concentration range investigated (50–500 nM), enabling a maximum reduction of 78% of the nonspecific current signal with respect to untreated SWCNT-SPEs for a 100 nM DNA sample. Incubation of the electrode surface with BSA, which is conventionally used as a blocking agent for passivation of gold electrodes and surfaces, also enabled significant reduction of the amperometric signal from nonspecific DNA adsorption (Figure 2c,d). However, BSA proved less effective than pyrene in reducing the nonspecific signal caused by DNA physisorption (57% vs 78% reduction of current signal with respect to pristine electrodes), which would lead to a lower sensitivity of the sensing platform. These results demonstrates that the nonspecific signal due to uncontrolled DNA physisorption cannot be eliminated and must therefore be considered when measuring and analyzing the amperometric outputs of E-DNAs based on SWCNT-SPEs. Treatment of the electrode surface with pyrene enabled a significant and reproducible reduction of this effect, so we included it as a standard operation in the preparation of DNA-functionalized SWCNT-SPEs.

Formation of Specific DNA Duplexes on the CNT Surface

We then investigated the controlled formation of DNA duplexes at the electrode surface and studied how to correctly interpret the signal resulting from the specific hybridization process. In this case, we used a sample solution of a DNA oligonucleotide with a sequence full complementary (full-match DNA) to that of the capture probe anchored to the electrode surface and conjugated with an Atto-MB2 redox tag at its 3′-terminus. As illustrated in Figure 3a, the formation of a duplex brings the tag redox of the full-match DNA near the electrode surface, promoting an efficient electron transfer process. We incubated DNA-functionalized SWCNT-SPE with different concentrations (30 nM to 500 nm) of complementary Atto-MB2-labeled DNA strands and recorded the resulting current signal (Figure 3b,c). In parallel, we systematically carried out the same experiments using a sample solution of a noncomplementary DNA oligonucleotide, which at each concentration allowed us to estimate the contribution to the final signal given by the nonspecific adsorption of the DNA strands onto the CNT surface. In this way, it was possible to determine the portion of the total amperometric output that is exclusively attributable to the formation of a duplex between complementary strands at the interface of the materials, which we have called hybridization current (Figure 3b,c). The hybridization current increased linearly when increasing the full-match DNA concentration from 30 to 100 nM, reached a maximum of 133 ± 11 nA at 100 nM and then dropped at higher concentrations of 300 and 500 nM (Figure 3c). Based on the calculated probe density of 4.3 × 1011 DNA probes/mm2, which results in ∼9 picomoles of DNA probes available on the whole electrode surface, using 50 μL of incubating solution generates a local probe concentration of around 180 nM. This explains why a maximum value of hybridization current is achieved when using a 100 nM full-match DNA solution. For the same reason, at higher concentrations of DNA, the CNT surface reaches a saturation point in terms of duplexes assembled at the interface, and a further contribution to the total current signal is given only by an increase in the nonspecific surface adsorption of the full-match DNA, leading to reduced values of the hybridization current (Figure 3c).

Figure 3

Figure 3. (a) Schematic drawing of the formation of specific DNA duplexes on the CNT electrode surface. MB is the Atto-MB2 redox tag. (b) Representative voltammograms obtained using a redox-tagged full-match DNA (100 nM) and a redox-tagged nonspecific DNA (100 nM), respectively. The difference between the two signals gives the hybridization current specific to the formed duplexes. (c) Hybridization current values obtained using different concentrations of full-match DNA (mean value ± sd, n = 3). (d) Linear fit of normalized hybridization currents for full-match DNA concentrations in the 30–100 nM range. Hybridization currents were normalized with respect to the most intense response recorded at the 100 nM concentration level.

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The hybridization current is a linear function of the concentration of full-match DNA in the 30–100 nM range, for which it was possible to determine the equation in = 0.14 (±0.05) + 0.0088 (±0.0007) [full-match DNA] (nM), where in is expressed as normalized hybridization current (Figure 3d). Based on the reported equation, a limit of detection (LOD) of 8 nM and a limit of quantification (LOQ) of 27 nM were calculated, respectively. These results show that an ideal working range for DNA-functionalized SWCNT-SPEs as hybridization platforms is identified in which the amperometric output can be expressed as the current signal derived exclusively from the formation of specific duplexes at the interface. Controlling hybridization processes at the interface enables the design of CNT-based electrochemical platforms in which programmable dynamic DNA systems can be engineered to provide an amperometric output in response to a nucleic acid input. DNA duplexes formed on the electrode surface can be designed to undergo strand displacement reactions in the presence of a third input strand. Toehold-mediated strand displacement is likely the most simple and versatile programmable process to carry out molecular operations enabling applications in sensing, information processing, and synthetic biology. (40−43)

Toehold-Mediated Strand Displacement Reactions

In the present work we engineered a strand displacement amperometric platform by assembling DNA duplexes on the CNT surface in which one strand is tagged with Atto-MB2 and presents a 6-nt-long toehold domain (Figure 4a).

Figure 4

Figure 4. (a) Schematic illustration of a toehold-mediated DNA strand displacement reaction conducted on the surface of SWCNT-SPEs, which can be monitored via amperometric measurements as an invader strand removes a redox-tagged strand near the electrode surface. MB is the Atto-MB2 redox tag. (b) Representative voltammograms recorded in the presence of different concentrations of the invader strand. (c) Relative hybridization current values measured in the presence of different concentrations of the invader strand (mean value ± sd, n = 3).

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A full complementary input strand to this latter, represented as the invader strand in Figure 4a, can then trigger a toehold-mediated strand displacement reaction leading to removal of the redox tag from the vicinity of the electrode surface. This process can be monitored directly through an amperometric measurement. Starting from duplexes obtained using a 100 nM concentration of redox-tagged oligonucleotide, the incubation of the electrode surface with different concentrations of the invader strand caused a reduction of the total current signal in accordance with the strand displacement mechanism (Figure 4b). (44) This translated in values of hybridization current, calculated as described above, which decreased proportionally with increasing concentrations of invader strand, with the strand displacement reaction proceeding at an almost quantitative rate (hybridization current reduced by 88% compared to that recorded in the absence of the invader strand) when using a 100 nM invader strand (Figure 4c). We then investigated the response of the strand displacement mechanism when in the presence of nontarget sequences. Three invader strand sequences were selected that were a completely random sequence, a three-mismatch sequence, and a single-mismatch sequence, these two latter bearing three or one noncomplementary nucleobases in the toehold region, respectively (sequences are reported in the SI). Incubation with the random sequence resulted in no decrease of the signal (Figure S5). In the case of the three-mismatch sequence, the reduction in the relative hybridization current was approximately 10%, whereas a more significant reduction in the relative hybridization current of around 70% was observed when in the presence of the single-mismatch sequence (Figure S5). Nevertheless, the hybridization current in this last case was still three times higher than that obtained, instead, when in the presence of a full-complementary invader strand at the same concentration, which shows that the presence of a single noncomplementary nucleobase in the invader strand leads to a decrease in the hybridization current to values that can still be distinguished from those given by a full-complementary invader sequence. It is also worth pointing out that the effect of mismatches in complementary DNA strands depends on the nature of the nucleobase substitution and on their position within the sequence. (45) For this reason, each sequence should be investigated independently when assessing the effect of mismatches on duplex stability and strand displacement efficiency. Since the sequences of the DNA strands used to form the functional duplexes on the electrode surface can be rationally designed to allow for a strand displacement reaction with a desired invader oligonucleotide sequence, it should be noted that it is possible to engineer SWCNT-SPEs into preloaded amperometric platforms with DNA duplexes that respond via a signal-off mechanism specifically to the presence of a target nucleic acid.

Artificial DNA Duplexes Templated by Melamine Enabling Toehold-Free Strand Exchange Reactions

Based on our ability to control DNA hybridization processes on the CNT electrode surface, we therefore set out to explore the possibility to use more complex nucleic acid structures and design amperometric hybridization platforms that support nucleic acid operations complementary to conventional toehold-mediated strand displacement reactions. For this purpose, we focused on small molecule-templated artificial DNA duplexes that were recently fully characterized by Chengde Mao and collaborators. (46) These are poly(thymine) (poly(T)) strands that self-associate into antiparallel, right-handed duplexes in the presence of a central pile of stacked melamine molecules as the latter provide a geometry of hydrogen bonding sites mimicking that of adenine. It was demonstrated that these structures are highly dynamic and can support toehold-free strand exchange reactions where poly(A) sequences, which bind tighter to poly(T) strands, replace the central melamine units causing a transition from the artificial melamine-templated duplex to a canonical poly(T)-poly(A) duplex. (46) Our first goal was then to assemble artificial poly(T)-melamine duplexes on the surface of SWCNT-SPEs (Figure 5a). Since the controlled assembly of these types of structures on the surface of materials substrates using two distinct poly(T) strands had never been reported, we decided to combine the functionalization protocols developed in this work with the rational design of a series of nucleic acid sequences to test.

Figure 5

Figure 5. (a) Schematic drawing of the controlled formation of artificial poly(T)-melamine duplexes on the surface of SWCNT-SPEs. (b) Table reporting the DNA sequences designed for the controlled assembly of poly(T)-melamine duplexes on the electrode surface. (c) Hybridization current values related to the artificial poly(T)-melamine duplexes obtained using 100 nM of 15-nt poly(T) sequences (0GC), 15-nt poly(T) sequences conjugated with 3 G/C bases (3GC), 15-nt poly(T) sequences conjugated with 6 G/C bases (6GC), respectively, in the presence of 1 mM melamine (mean value ± sd, n = 3). (d) Representative voltammograms obtained using 15(T)-3GC-duplex-forming strands (100 nM) in the presence (solid line) and in the absence (dashed line) of melamine (1 mM), respectively. The difference between the two signals is the hybridization current specific to the formed artificial poly(T)-melamine duplexes. (e) Schematic illustration of a strand exchange reaction conducted at the electrode surface, where a poly(A) strand replaces the central melamine units of an initial poly(T)-melamine duplex to form a canonical poly(T)-poly(A) duplex. (f) Representative voltammograms recorded in the presence (blue line) and in the absence (violet line) of a poly(A) sequence reacting with poly(T)-melamine duplexes previously assembled on the electrode surface. (g) Relative hybridization current values obtained upon incubation with a poly(A) invader strand (100 nM), showing that the induced strand exchange reaction is almost quantitative (mean value ± sd, n = 3).

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One strand was modified with an amine group and then anchored to the electrode surface, whereas the other was conjugated with Atto-MB2 to generate a current signal following the hybridization process (Figure 5b). In this regard, it should be noted that melamine is not electroactive in the same potential window of the Atto-MB2 redox tag and does not lead to any interference with the measured current signal (Figure S6). We have chosen to work with 15 bases long poly(T) strands because these can assemble into stable artificial duplexes in the presence of >5 equiv of melamine in solution and can form poly(T)-poly(A) duplexes as well at room temperature. (46) In addition to 15-nt homopoly(T) strands, we designed 18-nt and 21-nt sequences in which the 15-nt poly(T) core was flanked by additional 3 or 6 G or C bases, respectively (Figure 5b). This would allow us to investigate whether the presence of a set of bases that give the canonical Watson–Crick hydrogen bonding could provide additional driving force for the formation of artificial poly(T)-melamine duplexes on the electrode surface. For each sequence pair, the CNT electrode surface was functionalized with the amine-modified strand (500 nM), treated with pyrene (500 nM in DMSO) as a backfilling agent and eventually incubated with a complementary poly(T)-based strand (100 nM) in the presence of melamine (1 mM). The amperometric output specific to the formation of artificial poly(T)-melamine duplexes at the interface, that is, the hybridization current, was calculated as the difference between the signal recorded in the presence and in the absence of melamine (Figure 5c,d). Indeed, in this case, the experiments performed in the absence of melamine lead to current signals that are given exclusively by the nonspecific adsorption of the redox-tagged DNA strands on the electrode surface, allowing to calculate the hybridization current values in the same way as described above. When mirror image 15-mer poly(T) strands were used, the resulting hybridization current was quite low (19 ± 7 nA). In this case, we assume that artificial poly(T)-melamine duplexes can form both in solution and on the electrode surface, based on the same exact sequences. It is likely that self-assembly in solution was largely favored, making the concomitant surface formation of poly(T)-melamine structures just a marginal process. Conversely, the use of poly(T) sequences flanked by additional G and C bases led to hybridization current values around 100 nA, demonstrating that the introduction of complementary Watson–Crick base pairing is a helpful strategy to provide a driving force for the formation of poly(T)-melamine structures on the electrode surface. We observed that there was no statistically significant difference (p > 0.05) between the hybridization current obtained for the 3 GC- and the 6 GC-based molecular designs (Figure 5c), indicating that a set of 3 GC base pairs is sufficient to promote an interaction between the DNA probes anchored to the electrode surface and the strands in solution and to support the subsequent melamine-templated hybridization of the poly(T) regions (Figure 5d). Based on these results, we explored the possibility of performing and monitoring through direct amperometric measurements strand exchange reactions alternative to conventional toehold-mediated strand displacement reaction. To this aim, we engineered our hybridization amperometric platform by assembling poly(T)-melamine duplexes on the CNT surface using 5′-NH2-GGC-(T)15-3′ as a capture probe and 5′-(T)15-GCC-MB-3′ as its complementary sequence in the presence of melamine. A poly(A) 15-mer (poly(A) invader) can then serve as an input strand to break the preformed artificial poly(T)-melamine structures through the formation of thermodynamically favored canonical poly(T)-poly(A) duplexes, causing displacement of the redox tagged-strands and a reduction in the measurable current signal (Figure 5e). Starting from poly(T)-melamine duplexes obtained using a 100 nM concentration of the redox-tagged sequence, the incubation of the electrode surface with an equimolar concentration of the poly(A) invader led to a decrease in the total current signal according to the proposed mechanism (Figure 5f). The hybridization current, calculated as mentioned above, recorded upon addition of the poly(A) invader, was approximately 15% of that measured in its absence (Figure 5g), which shows that the strand exchange reaction conducted at the electrode surface was highly efficient. Of note, this is the first time that dynamic reactions of this type based on artificial poly(T)-melamine duplexes have been performed on the surface of a materials substrate.

Conclusion

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This study provides design rules and a research protocol for interfacing dynamic DNA systems with CNT-based electrodes. We have demonstrated that a strategy to limit unwanted nonspecific interactions between DNA strands and the CNT surface is key to developing a DNA/electrode interface that supports the unambiguous electrochemical detection of nucleic acid recognition events. Our results point out that a systematic evaluation of the nonspecific signal due to DNA physisorption on the electrode surface is instrumental to a correct interpretation of the electrochemical output specifically generated by the hybridization processes involving a target sequence. The protocols developed in the present work demonstrate that DNA strand displacement reactions can be designed and conducted on the CNT electrode surface and can be monitored through measurements of the specific hybridization current. This suggests that it will be possible to interface CNT-SPEs with more complex dynamic systems enabled by DNA nanotechnology for the engineering of new formats of E-DNAs and amperometric biosensors. (7,47,48) We applied our strategy to the assembly of artificial DNA structures based on poly(T) duplexes templated by the small molecule melamine. These allow for performing toehold-free strand exchange reactions triggered by a poly(A) sequence, which can be easily followed by measuring the resulting hybridization current. DNA structures based on poly(T) duplexes templated by the small molecule melamine are a recent discovery that has the potential to widen the available tools for programming DNA-based molecular systems and interfaces. The possibility to perform toehold-free strand exchange reactions that leverage a basic poly(A) sequence as the invader strand is particularly appealing for the development of sequence-independent electrochemical platforms enabling detection of non-nucleic-acid analytes. Many molecular systems have been recently developed in which generation or release of an arbitrary nucleic acid sequence can be controlled upstream by a specific protein, including antibodies, transcription factors, and other functional proteins. (41,49−53) An electrochemical platform designed to respond to an arbitrary protein-controlled poly(A)-based input by simple disassembly of poly(T)-melamine structures would require no efforts in sequence design, and it could be applied to any molecular system engineered to provide a poly(A) strand as a molecular output. Furthermore, more complex architectures based on the same strategy could be designed in which toehold-mediated and toehold-free reactions are performed in an orthogonal way, facilitating the design of molecular interfaces for multiplex analyses. Our results suggest also that alternative structures based on a similar principle, that is, small molecule- or metal-templated nucleic acid structures, may be controlled at the electrode surface, which could be useful in the design of new formats of sensors and portable electrochemical devices. (54,55) We envision that functional interfaces that use programmable DNA systems in conjunction with carbon nanotube substrates will support the development of new generations of electrochemical sensors and diagnostic devices integrating the advantageous physicochemical properties of nanostructured carbon-based materials with specific and predictable nucleic acid hybridization.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.1c05294.

  • DNA sequences, enzyme-based electrochemical signal, calculation of probe density, efficacy of electrode backfilling using pyrene, strand displacement using mismatched sequences, and melamine electroactivity in the potential range of interest (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Simone Fortunati - Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
    • Ilaria Vasini - Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
    • Marco Giannetto - Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy;  Orcidhttps://orcid.org/0000-0001-7031-7466
    • Monica Mattarozzi - Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
    • Alessandro Porchetta - Department of Chemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy;  Orcidhttps://orcid.org/0000-0002-4061-5574
    • Maria Careri - Department of Chemistry, Life Sciences, and Environmental Sustainability, University of Parma, 43124 Parma, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research benefited from equipment and core facilities provided by the COMP-HUB Initiative of the Department of Chemistry, Life Sciences and Environmental Sustainability of the University of Parma and funded by the “Departments of Excellence” program of the Italian Ministry for Education, University and Research (MIUR, 2018-2022). This research has financially been supported by the Programme “FIL-Quota Incentivante” of the University of Parma and cosponsored by Fondazione Cariparma (AB).

References

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    Das, J.; Ivanov, I.; Montermini, L.; Rak, J.; Sargent, E. H.; Kelley, S. O. An Electrochemical Clamp Assay for Direct, Rapid Analysis of Circulating Nucleic Acids in Serum. Nat. Chem. 2015, 7 (7), 569– 575,  DOI: 10.1038/nchem.2270
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    An electrochemical clamp assay for direct, rapid analysis of circulating nucleic acids in serum
    Das, Jagotamoy; Ivanov, Ivaylo; Montermini, Laura; Rak, Janusz; Sargent, Edward H.; Kelley, Shana O.
    Nature Chemistry (2015), 7 (7), 569-575CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The anal. of cell-free nucleic acids (cfNAs), which are present at significant levels in the blood of cancer patients, can reveal the mutational spectrum of a tumor without the need for invasive sampling of the tissue. However, this requires differentiation between the nucleic acids that originate from healthy cells and the mutated sequences shed by tumor cells. Here we report an electrochem. clamp assay that directly detects mutated sequences in patient serum. This is the first successful detection of cfNAs without the need for enzymic amplification, a step that normally requires extensive sample processing and is prone to interference. The new chip-based assay reads out the presence of mutations within 15 min using a collection of oligonucleotides that sequester closely related sequences in soln., and thus allow only the mutated sequence to bind to a chip-based sensor. We demonstrate excellent levels of sensitivity and specificity and show that the clamp assay accurately detects mutated sequences in a collection of samples taken from lung cancer and melanoma patients.
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  14. 14
    Gasparac, R.; Taft, B. J.; Lapierre-Devlin, M. A.; Lazareck, A. D.; Xu, J. M.; Kelley, S. O. Ultrasensitive Electrocatalytic DNA Detection at Two- and Three-Dimensional Nanoelectrodes. J. Am. Chem. Soc. 2004, 126 (39), 12270– 12271,  DOI: 10.1021/ja0458221
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    Ultrasensitive Electrocatalytic DNA Detection at Two- and Three-Dimensional Nanoelectrodes
    Gasparac, Rahela; Taft, Bradford J.; Lapierre-Devlin, Melissa A.; Lazareck, Adam D.; Xu, Jimmy M.; Kelley, Shana O.
    Journal of the American Chemical Society (2004), 126 (39), 12270-12271CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Electrochem. DNA detection systems are an attractive approach to the development of multiplexed, high-throughput DNA anal. systems for clin. and research applications. We have engineered a new class of nanoelectrode ensembles (NEEs) that constitute a useful platform for biomol. electrochem. sensing. High-sensitivity DNA detection was achieved at oligonucleotide-functionalized NEEs using a label-free electrocatalytic assay. Attomole-levels of DNA were detected using the NEEs, validating the promise of nanoarchitectures for ultrasensitive biosensing.
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  15. 15
    Pheeney, C. G.; Barton, J. K. DNA Electrochemistry with Tethered Methylene Blue. Langmuir 2012, 28 (17), 7063– 7070,  DOI: 10.1021/la300566x
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    DNA Electrochemistry with Tethered Methylene Blue
    Pheeney, Catrina G.; Barton, Jacqueline K.
    Langmuir (2012), 28 (17), 7063-7070CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Methylene blue (MB'), covalently attached to DNA through a flexible C12 alkyl linker, provides a sensitive redox reporter in DNA electrochem. measurements. Tethered, intercalated MB' is reduced through DNA-mediated charge transport; the incorporation of a single base mismatch at position 3, 10, or 14 of a 17-mer causes an attenuation of the signal to 62 ± 3% of the well-matched DNA, irresp. of position in the duplex. The redox signal intensity for MB'-DNA is found to be least 3-fold larger than that of Nile blue (NB)-DNA, indicating that MB' is even more strongly coupled to the π-stack. The signal attenuation due to an intervening mismatch does, however, depend on DNA film d. and the backfilling agent used to passivate the surface. These results highlight two mechanisms for redn. of MB' on the DNA-modified electrode: redn. mediated by the DNA base pair stack and direct surface redn. of MB' at the electrode. These two mechanisms are distinguished by their rates of electron transfer that differ by 20-fold. The extent of direct redn. at the surface can be controlled by assembly and buffer conditions.
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  16. 16
    Muren, N. B.; Barton, J. K. Electrochemical Assay for the Signal-On Detection of Human DNA Methyltransferase Activity. J. Am. Chem. Soc. 2013, 135 (44), 16632– 16640,  DOI: 10.1021/ja4085918
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    Electrochemical Assay for the Signal-On Detection of Human DNA Methyltransferase Activity
    Muren, Natalie B.; Barton, Jacqueline K.
    Journal of the American Chemical Society (2013), 135 (44), 16632-16640CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Strategies to detect human DNA methyltransferases are needed, given that aberrant methylation by these enzymes is assocd. with cancer initiation and progression. Here we describe a nonradioactive, antibody-free, electrochem. assay in which methyltransferase activity on DNA-modified electrodes confers protection from restriction for signal-on detection. We implement this assay with a multiplexed chip platform and show robust detection of both bacterial (SssI) and human (Dnmt1) methyltransferase activity. Essential to work with human methyltransferases, our unique assay design allows activity measurements on both unmethylated and hemimethylated DNA substrates. We validate this assay by comparison with a conventional radioactive method. The advantages of electrochem. over radioactivity and fluorescence make this assay an accessible and promising new approach for the sensitive, label-free detection of human methyltransferase activity.
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  17. 17
    Dubuisson, E.; Yang, Z.; Loh, K. P. Optimizing Label-Free DNA Electrical Detection on Graphene Platform. Anal. Chem. 2011, 83 (7), 2452– 2460,  DOI: 10.1021/ac102431d
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    17
    Optimizing Label-Free DNA Electrical Detection on Graphene Platform
    Dubuisson, Emilie; Yang, Zhiyong; Loh, Kian Ping
    Analytical Chemistry (Washington, DC, United States) (2011), 83 (7), 2452-2460CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The anodized epitaxial graphene (EG) electrode demonstrates a high level of performance for electrochem. impedance as well as differential pulse voltammetry detection of immobilized DNA and free DNA, resp., at solid-liq. interfaces. On the anodized EG surface, because of the presence of oxygen functionalities as well as π conjugated domains, the anchoring of the DNA probe can be achieved by either covalent grafting or noncovalent π-π stacking readily. The effect of different binding modes on the sensitivity of the impedimetric sensing was investigated. Equivalent circuit modeling shows that the sensitivity of EG to DNA hybridization is controlled by changes in the resistance of the mol. layer as well as the space charge layer. The linear dynamic detection range of EG for DNA oligonucleotides is in the range of 5.0 × 10-14 to 1 × 10-6 M. In addn., with the use of differential pulse voltammetry, single stranded DNA, fully complementary DNA, as well as single nucleotide polymorphisms can be differentiated on anodized EG by monitoring the oxidn. signals of individual nucleotide bases.
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  18. 18
    Campuzano, S.; Yáñez-Sedeño, P.; Pingarrón, J. M. Tailoring Sensitivity in Electrochemical Nucleic Acid Hybridization Biosensing: Role of Surface Chemistry and Labeling Strategies. ChemElectroChem. 2019, 6 (1), 60– 72,  DOI: 10.1002/celc.201800667
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    18
    Tailoring Sensitivity in Electrochemical Nucleic Acid Hybridization Biosensing: Role of Surface Chemistry and Labeling Strategies
    Campuzano, Susana; Yanez-Sedeno, Paloma; Pingarron, Jose Manuel
    ChemElectroChem (2019), 6 (1), 60-72CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Electrochem. nucleic acid hybridization biosensors have become a mainstay to detect DNA or RNA targets of interest in clin. diagnostics, environmental monitoring and food quality control. Despite the great progress they demonstrated during the last years, there is a const. demand to improve their performance, mainly in terms of sensitivity, simplicity of protocols and easy implementation in routine and decentralized detns. Within this context, the tremendous possibilities offered by both, a judicious interfacing of the electrode surface, and the use of innovative labeling strategies not requiring nanomaterials or nucleic acid amplification, is discussed critically in this review.
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  19. 19
    Michaels, P.; Alam, M. T.; Ciampi, S.; Rouesnel, W.; Parker, S. G.; Choudhury, M. H.; Gooding, J. J. A Robust DNA Interface on a Silicon Electrode. Chem. Commun. 2014, 50 (58), 7878– 7880,  DOI: 10.1039/C4CC03418J
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    19
    A robust DNA interface on a silicon electrode
    Michaels, Pauline; Alam, Muhammad Tanzirul; Ciampi, Simone; Rouesnel, William; Parker, Stephen G.; Choudhury, Moinul H.; Gooding, J. Justin
    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (58), 7878-7880CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Two different interfaces prepd. via UV-hydrosilylation of undecylenic acid and 1,8-nonadiyne on silicon(111) have been explored to develop a robust electrochem. DNA sensor. Electrodes modified with undecylenic acid stably immobilize DNA but could not resist the growth of insulating oxides, whereas 1,8-nonadiyne modified electrodes satisfy both requirements.
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    Ricci, F.; Zari, N.; Caprio, F.; Recine, S.; Amine, A.; Moscone, D.; Palleschi, G.; Plaxco, K. W. Surface Chemistry Effects on the Performance of an Electrochemical DNA Sensor. Bioelectrochemistry 2009, 76 (1–2), 208– 213,  DOI: 10.1016/j.bioelechem.2009.03.007
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    20
    Surface chemistry effects on the performance of an electrochemical DNA sensor
    Ricci, Francesco; Zari, Nadia; Caprio, Felice; Recine, Simona; Amine, Aziz; Moscone, Danila; Palleschi, Giuseppe; Plaxco, Kevin W.
    Bioelectrochemistry (2009), 76 (1-2), 208-213CODEN: BIOEFK; ISSN:1567-5394. (Elsevier B.V.)
    E-DNA sensors are a reagentless, electrochem. oligonucleotide sensing platform based on a redox-tag modified, electrode-bound probe DNA. Because E-DNA signaling is linked to hybridization-linked changes in the dynamics of this probe, sensor performance is likely dependent on the nature of the self-assembled monolayer coating the electrode. The authors have investigated this question by characterizing the gain, specificity, response time and shelf-life of E-DNA sensors fabricated using a range of co-adsorbates, including both charged and neutral alkane thiols. The authors find that, among the thiols tested, the pos. charged cysteamine gives rise to the largest and most rapid response to target and leads to significantly improved storage stability. The best mismatch specificity, however, is achieved with mercaptoethanesulfonic and mercaptoundecanol, presumably due to the destabilizing effects of, resp., the neg. charge and steric bulk of these co-adsorbates. These results demonstrate that a careful choice of co-adsorbate chem. can lead to significant improvements in the performance of this broad class of electrochem. DNA sensors.
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    Wang, J.; Musameh, M. Carbon Nanotube Screen-Printed Electrochemical Sensors. Analyst 2004, 129 (1), 1,  DOI: 10.1039/b313431h
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    Carbon nanotube screen-printed electrochemical sensors
    Wang, Joseph; Musameh, Mustafa
    Analyst (Cambridge, United Kingdom) (2004), 129 (1), 1-2CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
    The fabrication, and evaluation of C-nanotube (CNT)-derived screen-printed (SP) electrochem. sensors based on a CNT ink are reported. The fabricated CNT strips combine the attractive advantages of CNT materials and disposable screen-printed electrodes. Such thick-film CNT sensors have a well-defined appearance, are mech. stable, and exhibit high electrochem. reactivity.
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    Rasheed, P. A.; Sandhyarani, N. Carbon Nanostructures as Immobilization Platform for DNA: A Review on Current Progress in Electrochemical DNA Sensors. Biosens. Bioelectron. 2017, 97, 226– 237,  DOI: 10.1016/j.bios.2017.06.001
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    Carbon nanostructures as immobilization platform for DNA: A review on current progress in electrochemical DNA sensors
    Rasheed P Abdul; Sandhyarani N
    Biosensors & bioelectronics (2017), 97 (), 226-237 ISSN:.
    Development of a sensitive, specific and cost-effective DNA detection method is motivated by increasing demand for the early stage diagnosis of genetic diseases. Recent developments in the design and fabrication of efficient sensor platforms based on nanostructures make the highly sensitive sensors which could indicate very low detection limit to the level of few molecules, a realistic possibility. Electrochemical detection methods are widely used in DNA diagnostics as it provide simple, accurate and inexpensive platform for DNA detection. In addition, the electrochemical DNA sensors provide direct electronic signal without the use of expensive signal transduction equipment and facilitates the immobilization of single stranded DNA (ssDNA) probe sequences on a wide variety of electrode substrates. It has been found that a range of nanomaterials such as metal nanoparticles (MNPs), carbon based nanomaterials, quantum dots (QDs), magnetic nanoparticles and polymeric NPs have been introduced in the sensor design to enhance the sensing performance of electrochemical DNA sensor. In this review, we discuss recent progress in the design and fabrication of efficient electrochemical genosensors based on carbon nanostructures such as carbon nanotubes, graphene, graphene oxide and nanodiamonds.
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  23. 23
    Giannetto, M.; Bianchi, M. V.; Mattarozzi, M.; Careri, M. Competitive Amperometric Immunosensor for Determination of P53 Protein in Urine with Carbon Nanotubes/Gold Nanoparticles Screen-Printed Electrodes: A Potential Rapid and Noninvasive Screening Tool for Early Diagnosis of Urinary Tract Carcinoma. Anal. Chim. Acta 2017, 991, 133– 141,  DOI: 10.1016/j.aca.2017.09.005
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    23
    Competitive amperometric immunosensor for determination of p53 protein in urine with carbon nanotubes/gold nanoparticles screen-printed electrodes: A potential rapid and noninvasive screening tool for early diagnosis of urinary tract carcinoma
    Giannetto, Marco; Bianchi, Maria Vittoria; Mattarozzi, Monica; Careri, Maria
    Analytica Chimica Acta (2017), 991 (), 133-141CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
    Since p53 protein has become recognized biomarker for both diagnostic and therapeutic purposes in oncol. diseases with particular relevance for bladder cancer, it is highly desirable to search for a novel sensing tool for detecting the patient's p53 level at the early stage. Here the authors report the first study on the development and validation of a novel disposable competitive amperometric immunosensor for detn. of p53 protein at subnanomolar levels, based on p53 immobilization on gold nanoparticles/carbon nanotubes modified screen-printed carbon electrodes. The assay protocol requires the use of single anti-p53 mouse monoclonal antibody (DO-7 clone), able to recognize both wild-type and mutant p53. The developed immunosensor as well as the protocol of the electrochem. immunoassay were optimized by an exptl. design procedure to assess the suitability of the device to be validated and applied for the detn. of p53 in untreated and undiluted urine samples. The developed competitive immunodevice was able to achieve wide linear range detection of wild-type p53 from 20 pM to 10 nM with a low detection limit of 14 pM in synthetic urine samples, suggesting the sensor's capability of working in a complex sample matrix. The excellent performance results also in terms of selectivity, trueness and precision, coupled with the advantages of an easy prepn. and low-cost assay in contrast to other methods which require very complex, time-consuming and costly nanostructured architectures, makes the developed competitive immunosensor an anal. robust diagnostic tool, valuable for implementation of screening and follow-up programs in patients with urol. malignancies.
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    Fortunati, S.; Rozzi, A.; Curti, F.; Giannetto, M.; Corradini, R.; Careri, M. Single-Walled Carbon Nanotubes as Enhancing Substrates for PNA-Based Amperometric Genosensors. Sensors 2019, 19 (3), 588,  DOI: 10.3390/s19030588
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    24
    Single-walled carbon nanotubes as enhancing substrates for PNA-based amperometric genosensors
    Fortunati, Simone; Rozzi, Andrea; Curti, Federica; Giannetto, Marco; Corradini, Roberto; Careri, Maria
    Sensors (2019), 19 (3), 588/1-588/9CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)
    A new amperometric sandwich-format genosensor has been implemented on single-walled carbon nanotubes screen printed electrodes (SWCNT-SPEs) and compared in terms of performance with analogous genoassays developed using the same methodol. on non-nanostructured glassy carbon platforms (GC-SPE). The working principle of the genosensors is based on the covalent immobilization of Peptide Nucleic Acid (PNA) capture probes (CP) on the electrode surface, carried out through the carboxylic functions present on SWCNT-SPEs (carboxylated SWCNT) or electrochem. induced on GC-SPEs. The sequence of the CP was complementary to a 20-mer portion of the target DNA; a second biotin-tagged PNA signalling probe (SP), with sequence complementary to a different contiguous portion of the target DNA, was used to obtain a sandwich hybrid with an Alk. Phosphatase-streptavidin conjugate (ALP-Strp). Comparison of the responses obtained from the SWCNT-SPEs with those produced from the non-nanostructured substrates evidenced the remarkable enhancement effect given by the nanostructured electrode platforms, achieved both in terms of loading capability of PNA probes and amplification of the electron transfer phenomena exploited for the signal transduction, giving rise to more than four-fold higher sensitivity when using SWCNT-SPEs. The nanostructured substrate allowed to reach limit of detection (LOD) of 71 pM and limit of quantitation (LOQ) of 256 pM, while the corresponding values obtained with GC-SPEs were 430 pM and 1.43 nM, resp.
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    Hu, C.; Zhang, Y.; Bao, G.; Zhang, Y.; Liu, M.; Wang, Z. L. DNA Functionalized Single-Walled Carbon Nanotubes for Electrochemical Detection. J. Phys. Chem. B 2005, 109 (43), 20072– 20076,  DOI: 10.1021/jp0550457
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    DNA Functionalized Single-Walled Carbon Nanotubes for Electrochemical Detection
    Hu, Chenguo; Zhang, Yiyi; Bao, Gang; Zhang, Yuelan; Liu, Meilin; Wang, Zhong Lin
    Journal of Physical Chemistry B (2005), 109 (43), 20072-20076CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    Single-walled carbon nanotubes (SWNTs) were effectively dispersed and functionalized by wrapping with single-stranded DNA (ssDNA). The ssDNA-SWNTs attach strongly on glass substrate and easily form a uniform film, making it possible for electrochem. anal. and sensing. The film was fabricated into a working electrode, which exhibited good electrochem. voltammetric properties, such as flat and wide potential window, well-defined quasi-reversible voltammetric responses, and quick electron transfer for a Fe(CN)63-/Fe(CN)64 system, indicating that the ssDNA-SWNTs film should be a good anal. electrode for electrochem. detection or sensing. This was demonstrated by highly selective and sensitive detection of a low concn. of dopamine in the presence of excess ascorbic acid.
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    Zhang, X.; Jiao, K.; Liu, S.; Hu, Y. Readily Reusable Electrochemical DNA Hybridization Biosensor Based on the Interaction of DNA with Single-Walled Carbon Nanotubes. Anal. Chem. 2009, 81 (15), 6006– 6012,  DOI: 10.1021/ac802026j
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    26
    Readily reusable electrochemical DNA hybridization biosensor based on the interaction of DNA with single-walled carbon nanotubes
    Zhang, Xuzhi; Jiao, Kui; Liu, Shufeng; Hu, Yuwei
    Analytical Chemistry (Washington, DC, United States) (2009), 81 (15), 6006-6012CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Carboxylic group-functionalized single-walled carbon nanotubes (SWNTs) were assembled vertically on the glassy carbon electrode using ethylenediamine as linking agent to fabricate an aligned electrode (SWNTE). Single-stranded DNA (ssDNA) wrapped around the SWNTs to form ssDNA-wrapped SWNTE structures based on the interaction between ssDNA and SWNT. A sensitive differential pulse voltammetric (DPV) response was obtained at the ssDNA-wrapped SWNTE owing to the electrooxidn. of guanine bases. Double-stranded DNA (dsDNA) was formed when ssDNA on the ssDNA-wrapped SWNTE was hybridized with complementary ssDNA (cDNA). The dsDNA was removed from the SWNTs by undergoing a process of preconditioning at -0.6 V. Consequentially, the DPV response of guanine bases decreased. The used SWNTE could be renewed easily via ultrasonically rinsing. On the basis of this mechanism, a label-free and readily reusable electrochem. DNA hybridization biosensor was designed by directly monitoring the current change of guanine bases. Under optimum conditions, the plot of the measurement signal of guanine bases vs. the cDNA concns. was a good straight line in the range of 40-110 nM with a detection limit of 20 nM (3s). The biosensor can be switched to detect different target DNAs easily.
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    Ye, Y.; Ju, H. Rapid Detection of SsDNA and RNA Using Multi-Walled Carbon Nanotubes Modified Screen-Printed Carbon Electrode. Biosens. Bioelectron. 2005, 21 (5), 735– 741,  DOI: 10.1016/j.bios.2005.01.004
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    27
    Rapid detection of ssDNA and RNA using multi-walled carbon nanotubes modified screen-printed carbon electrode
    Ye, Yongkang; Ju, Huangxian
    Biosensors & Bioelectronics (2005), 21 (5), 735-741CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    A method for rapid sensitive detection of DNA or RNA was designed using a composite screen-printed carbon electrode modified with multi-walled carbon nanotubes (MWNTs). MWNTs showed catalytic characteristics for the direct electrochem. oxidn. of guanine or adenine residues of single strand DNA (ssDNA) and adenine residues of RNA, leading to indicator-free detection of ssDNA and RNA concns. With an accumulation time of 5 min, the proposed method could be used for detection of calf thymus ssDNA ranging from 17.0 to 345 μg mL-1 with a detection limit of 2.0 μg ml-1 at 3σ and yeast tRNA ranging from 8.2 μg mL-1 to 4.1 mg mL-1. AC impedance was employed to characterize the surface of modified electrodes. The advantages of convenient fabrication, low-cost detection, short anal. time and combination with nanotechnol. for increasing the sensitivity made the subject worthy of special emphasis in the research programs and sources of new com. products.
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    Jiang, H.; Lee, E.-C. Highly Selective, Reusable Electrochemical Impedimetric DNA Sensors Based on Carbon Nanotube/Polymer Composite Electrode without Surface Modification. Biosens. Bioelectron. 2018, 118, 16– 22,  DOI: 10.1016/j.bios.2018.07.037
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    28
    Highly selective, reusable electrochemical impedimetric DNA sensors based on carbon nanotube/polymer composite electrode without surface modification
    Jiang, Huaide; Lee, Eun-Cheol
    Biosensors & Bioelectronics (2018), 118 (), 16-22CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    We fabricated a composite of multi-walled carbon nanotube and polydimethylsiloxane and utilized it as an electrode for DNA sensing using electrochem. impedance spectroscopy. Without any surface modification or probe immobilization, often necessary for other electrodes, this electrode also acts as a recognition layer for DNA via p-p interactions between the multi-walled carbon nanotube and DNA. This electrode is easily reusable via a simple cleansing process, because there are no covalently bonded adsorbates on the electrode. Compared to previous DNA detection based on differential pulse voltammetry using a similar electrode, the measurement time was reduced from 1h to less than 30min, and the limit of detection (25pM) was reduced by a factor of more than five. In addn., our system can detect the single-base mismatch between the target and probe. Our results indicate that electrochem. impedance spectroscopy is promising for utilizing the multi-walled carbon nanotube and polydimethylsiloxane electrode as a DNA sensor.
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    Weber, J. E.; Pillai, S.; Ram, M. K.; Kumar, A.; Singh, S. R. Electrochemical Impedance-Based DNA Sensor Using a Modified Single Walled Carbon Nanotube Electrode. Mater. Sci. Eng., C 2011, 31 (5), 821– 825,  DOI: 10.1016/j.msec.2010.12.009
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    29
    Electrochemical impedance-based DNA sensor using a modified single walled carbon nanotube electrode
    Weber, Jessica E.; Pillai, Shreekumar; Ram, Manoj Kumar; Kumar, Ashok; Singh, Shree R.
    Materials Science & Engineering, C: Materials for Biological Applications (2011), 31 (5), 821-825CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
    Carbon nanotubes have become promising functional materials for the development of advanced electrochem. biosensors with novel features which could promote electron-transfer with various redox active biomols. This paper presents the detection of Salmonella enterica serovar Typhimurium using chem. modified single walled carbon nanotubes (SWNTs) with single stranded DNA (ssDNA) on a polished glassy carbon electrode. Hybridization with the corresponding complementary ssDNA has shown a shift in the impedance studies due to a higher charge transfer in ssDNA. The developed biosensor has revealed an excellent specificity for the appropriate targeted DNA strand. The methodologies to prep. and functionalize the electrode could be adopted in the development of DNA hybridization biosensor.
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  30. 30
    Bonanni, A.; Esplandiu, M. J.; del Valle, M. Impedimetric Genosensors Employing COOH-Modified Carbon Nanotube Screen-Printed Electrodes. Biosens. Bioelectron. 2009, 24 (9), 2885– 2891,  DOI: 10.1016/j.bios.2009.02.023
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    30
    Impedimetric genosensors employing COOH-modified carbon nanotube screen-printed electrodes
    Bonanni, A.; Esplandiu, M. J.; del Valle, M.
    Biosensors & Bioelectronics (2009), 24 (9), 2885-2891CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    Screen-printed electrodes modified with carboxyl functionalized multi-walled carbon nanotubes were used as platforms for impedimetric genosensing of oligonucleotide sequences specific for transgenic insect resistant Bt maize. After covalent immobilization of aminated DNA probe using carbodiimide chem., the impedance measurement was performed in a soln. contg. the redox marker ferrocyanide/ferricyanide. A complementary oligomer (target) was then added, its hybridization was promoted and the measurement performed as before. The change of interfacial charge transfer resistance between the soln. and the electrode surface, experimented by the redox marker at the applied potential, was recorded to confirm the hybrid formation. Non-complementary DNA sequences contg. a different no. of base mismatches were also employed in the expts. in order to test specificity. A signal amplification protocol was then performed, using a biotinylated complementary target to capture streptavidin modified gold nanoparticles, thus increasing the final impedimetric signal (LOD improved from 72 to 22 fmol, maintaining a good reproducibility, in fact RSD < 12.8% in all examd. cases). In order to visualize the presence and distribution of gold nanoparticles, a silver enhancement treatment was applied to electrodes already modified with DNA-nanoparticles conjugate, allowing direct observation by SEM.
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  31. 31
    Li, C.; Karadeniz, H.; Canavar, E.; Erdem, A. Electrochemical Sensing of Label Free DNA Hybridization Related to Breast Cancer 1 Gene at Disposable Sensor Platforms Modified with Single Walled Carbon Nanotubes. Electrochim. Acta 2012, 82, 137– 142,  DOI: 10.1016/j.electacta.2012.05.057
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    Electrochemical sensing of label free DNA hybridization related to breast cancer 1 gene at disposable sensor platforms modified with single walled carbon nanotubes
    Li, Chen-zhong; Karadeniz, Hakan; Canavar, Ece; Erdem, Arzum
    Electrochimica Acta (2012), 82 (), 137-142CODEN: ELCAAV; ISSN:0013-4686. (Elsevier Ltd.)
    The electrochem. monitoring of DNA hybridization related to specific sequences on breast cancer 1 (BRCA1) DNA by using single-walled C nanotube (SWCNT) based screen printed graphite electrodes (SPEs) was performed. After the microscopic characterization of SWCNT-SPE, the optimization of assay was studied. The development of screen printing process combined with nanomaterial based disposable sensor technol. with sensitivity, selectivity and reproducibility, has a great opportunity for DNA detection using differential pulse voltammetry (DPV) by measuring the guanine oxidn. signal obsd. at +1.00 V in the presence of DNA hybridization between BRCA1 probe and its complementary target. The detection limit estd. for signal to noise ratio = 3 corresponds to 378.52 nM target concn. in the 40 μL samples. The voltammetric results on BRCA1 DNA hybridization were also complemented with electrochem. impedance spectroscopy (EIS).
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  32. 32
    Karadeniz, H.; Erdem, A.; Caliskan, A. Electrochemical Monitoring of DNA Hybridization by Multiwalled Carbon Nanotube Based Screen Printed Electrodes. Electroanalysis 2008, 20 (17), 1932– 1938,  DOI: 10.1002/elan.200804270
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    Electrochemical monitoring of DNA hybridization by multiwalled carbon nanotube based screen printed electrodes
    Karadeniz, Hakan; Erdem, Arzum; Caliskan, Ayfer
    Electroanalysis (2008), 20 (17), 1932-1938CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The application of multiwalled carbon nanotube (MWCNT) based screen printed graphite electrodes (SPEs) was explored in this study for the electrochem. monitoring of DNA hybridization related to specific sequences on Hepatitis B virus (HBV) DNA. After the microscopic characterization of bare MWCNT-SPEs and DNA immobilized ones was performed, the optimization of assay has been studied. The development of screen printing process combined with nanomaterial based disposable sensor technol. leads herein a great opportunity for DNA detection using differential pulse voltammetry (DPV) by measuring the guanine oxidn. signal obsd. at +1.00 V in the presence of DNA hybridization between HBV probe and its complementary, target. The detection limit estd. for signal to noise ratios = 3 corresponds to 96.33 nM target concn. in the 40 μL samples. The advantages of carbon nanotube based screen printed electrode used for electrochem. monitoring of DNA hybridization are discussed with sensitivity, selectivity and reproducibility in comparison with previous nanomaterial based electrochem. transducers developed for DNA or other biomol. recognitions.
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  33. 33
    Cai, H.; Cao, X.; Jiang, Y.; He, P.; Fang, Y. Carbon Nanotube-Enhanced Electrochemical DNA Biosensor for DNA Hybridization Detection. Anal. Bioanal. Chem. 2003, 375 (2), 287– 293,  DOI: 10.1007/s00216-002-1652-9
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    Carbon nanotube-enhanced electrochemical DNA biosensor for DNA hybridization detection
    Cai, Hong; Cao, Xuni; Jiang, Ying; He, Pingang; Fang, Yuzhi
    Analytical and Bioanalytical Chemistry (2003), 375 (2), 287-293CODEN: ABCNBP; ISSN:1618-2642. (Springer-Verlag)
    A novel and sensitive electrochem. DNA biosensor based on multi-walled carbon nanotubes functionalized with a carboxylic acid group (MWNTs-COOH) for covalent DNA immobilization and enhanced hybridization detection is described. The MWNTs-COOH-modified glassy carbon electrode (GCE) was fabricated and oligonucleotides with the 5'-amino group were covalently bonded to the carboxyl group of carbon nanotubes. The hybridization reaction on the electrode was monitored by differential pulse voltammetry (DPV) anal. using an electroactive intercalator daunomycin as an indicator. Compared with previous DNA sensors with oligonucleotides directly incorporated on carbon electrodes, this carbon nanotube-based assay with its large surface area and good charge-transport characteristics dramatically increased DNA attachment quantity and complementary DNA detection sensitivity. This is the first application of carbon nanotubes to the fabrication of an electrochem. DNA biosensor with a favorable performance for the rapid detection of specific hybridization.
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  34. 34
    Erdem, A.; Papakonstantinou, P.; Murphy, H. Direct DNA Hybridization at Disposable Graphite Electrodes Modified with Carbon Nanotubes. Anal. Chem. 2006, 78 (18), 6656– 6659,  DOI: 10.1021/ac060202z
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    Direct DNA Hybridization at Disposable Graphite Electrodes Modified with Carbon Nanotubes
    Erdem, Arzum; Papakonstantinou, Pagona; Murphy, Hayley
    Analytical Chemistry (2006), 78 (18), 6656-6659CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The performance of glassy carbon (GCE) and graphite pencil electrodes (PGE) modified with multiwalled carbon nanotubes (CNTs) are compared, based on the direct electrochem. detection of nucleic acids. This is accomplished by monitoring the differential pulse voltammetry changes of the guanine signal. CNT-modified PGE compares favorably to that of the commonly used CNT-modified GCE owing to the intrinsic improved performance of the supporting PGE. The better intrinsic characteristics of the PGE are related to its composite structure and higher level of porosity compared to GCE. The performance characteristics of the direct DNA hybridization on the disposable CNT-modified PGE are studied in terms of optimum anal. conditions such as probe concn., target concn., hybridization time, and selectivity. The new DNA biosensor described here has shown some important advantages such being inexpensive, sensitive, selective, and able to generate reproducible results using a simple and direct electrochem. protocol.
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  35. 35
    Fortunati, S.; Rozzi, A.; Curti, F.; Giannetto, M.; Corradini, R.; Careri, M. Novel Amperometric Genosensor Based on Peptide Nucleic Acid (PNA) Probes Immobilized on Carbon Nanotubes-Screen Printed Electrodes for the Determination of Trace Levels of Non-Amplified DNA in Genetically Modified (GM) Soy. Biosens. Bioelectron. 2019, 129, 7– 14,  DOI: 10.1016/j.bios.2019.01.020
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    35
    Novel amperometric genosensor based on peptide nucleic acid (PNA) probes immobilized on carbon nanotubes-screen printed electrodes for the determination of trace levels of non-amplified DNA in genetically modified (GM) soy
    Fortunati, Simone; Rozzi, Andrea; Curti, Federica; Giannetto, Marco; Corradini, Roberto; Careri, Maria
    Biosensors & Bioelectronics (2019), 129 (), 7-14CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    A novel amperometric genosensor based on PNA probes covalently bound on the surface of Single Walled Carbon Nanotubes - Screen Printed Electrodes (SWCNT-SPEs) was developed and validated in samples of non-amplified genomic DNA extd. from genetically modified (GM)-Soy. The sandwich assay is based on a first recognition of a 20-mer portion of the target DNA by a complementary PNA Capture Probe (CP) and a second hybridization with a PNA Signalling Probe (SP), with a complementary sequence to a different portion of the target DNA. The SP was labeled with biotin to measure current signal by means of a final incubation of an Alk. Phosphatase-streptavidin conjugate (ALP-Strp). The electrochem. detection was carried out using hydroquinone diphosphate (HQDP) as enzymic substrate. The genoassay provided a linear range from 250 pM to 2.5 nM, LOD of 64 pM and LOQ of 215 pM Excellent selectivity towards one base mismatch (1-MM) or scrambled (SCR) sequences was obtained. A simple protocol for extn. and anal. of non-amplified soybean genomic DNA without sample treatment was developed and validated. Our study provides insight into how the outstanding recognition efficiency of PNAs can be combined with the unique properties of CNTs in terms of signal response enhancement for direct detection of genomic DNA samples at the level of interest without previous amplification.
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  36. 36
    Liu, X.; Shuai, H.-L.; Liu, Y.-J.; Huang, K.-J. An Electrochemical Biosensor for DNA Detection Based on Tungsten Disulfide/Multi-Walled Carbon Nanotube Composites and Hybridization Chain Reaction Amplification. Sensors Actuators B Chem. 2016, 235, 603– 613,  DOI: 10.1016/j.snb.2016.05.132
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    36
    An electrochemical biosensor for DNA detection based on tungsten disulfide/multi-walled carbon nanotube composites and hybridization chain reaction amplification
    Liu, Xue; Shuai, Hong-Lei; Liu, Yu-Jie; Huang, Ke-Jing
    Sensors and Actuators, B: Chemical (2016), 235 (), 603-613CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
    We report the prepn. and characterization of tungsten disulfide-multi-walled carbon nanotubes (WS2-MWCNTs) composite via a simple hydrothermal process and demonstrate its application as a biosensing platform for ultrasensitive detn. of hepatitis B virus genomic DNA coupled with hybridization chain reaction (HCR) signal amplification. The sensing platform includes capture DNA probe (cDNA), auxiliary DNA, two DNA hairpins, and detection signal is amplified by horse radish peroxidase (HRP) on the DNA duplex. The biosensor is fabricated with the cDNA labeled at 3' end using thiol immobilized on the WS2-MWCNTs/Au nanoparticels modified electrode. CDNA fixed onto electrode surface then reacts with target DNA through the 3 end of auxiliary DNA. The remaining segment on 5' end of auxiliary DNA then takes turns to open two alternating DNA hairpins. This leads to a HCR events to produce a nicked double-helix. A large amt. of HRP is then combined on DNA helix by affinity interaction of biotin-avidin, each of which amplifies the final electrochem. signal through the catalytic reaction of H2O2 and hydroquinol. Under optimal conditions, a dynamic range of 10 fM-0.1 nM is obtained with a detection limit of 2.5 fM. Synergistic effect of WS2-MWCNTs composite and HCR have proven to greatly improve sensitivity for DNA detection.
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    Magnusson, B. The Fitness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics. Eurachem Guidel. 2014, na
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    Keighley, S. D.; Li, P.; Estrela, P.; Migliorato, P. Optimization of DNA Immobilization on Gold Electrodes for Label-Free Detection by Electrochemical Impedance Spectroscopy. Biosens. Bioelectron. 2008, 23 (8), 1291– 1297,  DOI: 10.1016/j.bios.2007.11.012
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    Optimization of DNA immobilization on gold electrodes for label-free detection by electrochemical impedance spectroscopy
    Keighley, Simon D.; Li, Peng; Estrela, Pedro; Migliorato, Piero
    Biosensors & Bioelectronics (2008), 23 (8), 1291-1297CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    The ability to immobilize DNA probes onto gold substrates at an optimum surface d. is key in the development of a wide range of DNA biosensors. We present a method to accurately control probe DNA surface d. by the simultaneous co-immobilization of thiol modified probes and mercaptohexanol. Probe surface d. is controlled by the thiol molar ratio in soln., with a linear relationship between thiol molar ratio and probe d. spanning (1-9) × 1012/cm2. The probe surface d. per microscopic surface area was detd. using chronocoulometry, and a detailed anal. of the method presented. Using this sample prepn. method, the effect of probe d. and hybridization on the charge transfer resistance with the neg. charged ferri/ferrocyanide redox couple was detd. Above a threshold probe surface d. of 2.5 × 1012/cm2, electrostatic repulsion from the neg. charged DNA modulates the charge transfer resistance, allowing hybridization to be detected. Below the threshold d. no change in charge transfer resistance with probe d. or with hybridization occurs. The probe surface d. was optimized to obtain the max. percentage change in charge transfer resistance with hybridization.
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    Kim, H. S.; Farmer, B. L.; Yingling, Y. G. Effect of Graphene Oxidation Rate on Adsorption of Poly-Thymine Single Stranded DNA. Adv. Mater. Interfaces 2017, 4 (8), 1601168,  DOI: 10.1002/admi.201601168
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    Zhang, D. Y.; Seelig, G. Dynamic DNA Nanotechnology Using Strand-Displacement Reactions. Nat. Chem. 2011, 3 (2), 103– 113,  DOI: 10.1038/nchem.957
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    Dynamic DNA nanotechnology using strand-displacement reactions
    Zhang, David Yu; Seelig, Georg
    Nature Chemistry (2011), 3 (2), 103-113CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    A review. The specificity and predictability of Watson-Crick base pairing make DNA a powerful and versatile material for engineering at the nanoscale. This has enabled the construction of a diverse and rapidly growing set of DNA nanostructures and nanodevices through the programmed hybridization of complementary strands. Although it had initially focused on the self-assembly of static structures, DNA nanotechnol. is now also becoming increasingly attractive for engineering systems with interesting dynamic properties. Various devices, including circuits, catalytic amplifiers, autonomous mol. motors and reconfigurable nanostructures, have recently been rationally designed to use DNA strand-displacement reactions, in which two strands with partial or full complementarity hybridize, displacing in the process one or more pre-hybridized strands. This mechanism allows for the kinetic control of reaction pathways. Here, the authors review DNA strand-displacement-based devices, and look at how this relatively simple mechanism can lead to a surprising diversity of dynamic behavior.
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    Bertucci, A.; Porchetta, A.; Del Grosso, E.; Patiño, T.; Idili, A.; Ricci, F. Protein-Controlled Actuation of Dynamic Nucleic Acid Networks by Using Synthetic DNA Translators. Angew. Chem., Int. Ed. 2020, 59 (46), 20577– 20581,  DOI: 10.1002/anie.202008553
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    Protein-Controlled Actuation of Dynamic Nucleic Acid Networks by Using Synthetic DNA Translators
    Bertucci, Alessandro; Porchetta, Alessandro; Del Grosso, Erica; Patino, Tania; Idili, Andrea; Ricci, Francesco
    Angewandte Chemie, International Edition (2020), 59 (46), 20577-20581CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Integrating dynamic DNA nanotechnol. with protein-controlled actuation will expand the authors' ability to process mol. information. The authors have developed a strategy to actuate strand displacement reactions using DNA-binding proteins by engineering synthetic DNA translators that convert specific protein-binding events into trigger inputs through a programmed conformational change. The authors have constructed synthetic DNA networks responsive to two different DNA-binding proteins, TATA-binding protein and Myc-Max, and demonstrated multi-input activation of strand displacement reactions. The authors achieved protein-controlled regulation of a synthetic RNA and of an enzyme through artificial DNA-based communication, showing the potential of the authors' mol. system in performing further programmable tasks.
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    Hwang, M. T.; Landon, P. B.; Lee, J.; Choi, D.; Mo, A. H.; Glinsky, G.; Lal, R. Highly Specific SNP Detection Using 2D Graphene Electronics and DNA Strand Displacement. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (26), 7088– 7093,  DOI: 10.1073/pnas.1603753113
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    Highly specific SNP detection using 2D graphene electronics and DNA strand displacement
    Hwang, Michael T.; Landon, Preston B.; Lee, Joon; Choi, Duyoung; Mo, Alexander H.; Glinsky, Gennadi; Lal, Ratnesh
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (26), 7088-7093CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Single-nucleotide polymorphisms (SNPs) in a gene sequence are markers for a variety of human diseases. Detection of SNPs with high specificity and sensitivity is essential for effective practical implementation of personalized medicine. Current DNA sequencing, including SNP detection, primarily uses enzyme-based methods or fluorophore-labeled assays that are time-consuming, need lab.-scale settings, and are expensive. Previously reported elec. charge-based SNP detectors have insufficient specificity and accuracy, limiting their effectiveness. Here, we demonstrate the use of a DNA strand displacement-based probe on a graphene field effect transistor (FET) for high-specificity, single-nucleotide mismatch detection. The single mismatch was detected by measuring strand displacement-induced resistance (and hence current) change and Dirac point shift in a graphene FET. SNP detection in large double-helix DNA strands (e.g., 47 nt) minimize false-pos. results. Our elec. sensor-based SNP detection technol., without labeling and without apparent cross-hybridization artifacts, would allow fast, sensitive, and portable SNP detection with single-nucleotide resoln. The technol. will have a wide range of applications in digital and implantable biosensors and high-throughput DNA genotyping, with transformative implications for personalized medicine.
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    Lv, H.; Li, Q.; Shi, J.; Fan, C.; Wang, F. Biocomputing Based on DNA Strand Displacement Reactions. ChemPhysChem 2021, 22 (12), 1151– 1166,  DOI: 10.1002/cphc.202100140
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    Biocomputing Based on DNA Strand Displacement Reactions
    Lv, Hui; Li, Qian; Shi, Jiye; Fan, Chunhai; Wang, Fei
    ChemPhysChem (2021), 22 (12), 1151-1166CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The high sequence specificity and precise base complementary pairing principle of DNA provides a rich orthogonal mol. library for mol. programming, making it one of the most promising materials for developing bio-compatible intelligence. In recent years, DNA has been extensively studied and applied in the field of biol. computing. Among them, the toehold-mediated strand displacement reaction (SDR) with properties including enzyme free, flexible design and precise control, have been extensively used to construct biol. computing circuits. This review provides a systemic overview of SDR design principles and the applications. Strategies for designing DNA-only, enzymes-assisted, other mols.-involved and external stimuli-controlled SDRs are described. The recently realized computing functions and the application of DNA computing in other fields are introduced. Finally, the advantages and challenges of SDR-based computing are discussed.
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    Dunn, K. E.; Trefzer, M. A.; Johnson, S.; Tyrrell, A. M. Investigating the Dynamics of Surface-Immobilized DNA Nanomachines. Sci. Rep. 2016, 6 (1), 29581,  DOI: 10.1038/srep29581
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    Investigating the dynamics of surface-immobilized DNA nanomachines
    Dunn, Katherine E.; Trefzer, Martin A.; Johnson, Steven; Tyrrell, Andy M.
    Scientific Reports (2016), 6 (), 29581CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    Surface-immobilization of mols. can have a profound influence on their structure, function and dynamics. Toehold-mediated strand displacement is often used in soln. to drive synthetic nanomachines made from DNA, but the effects of surface-immobilization on the mechanism and kinetics of this reaction have not yet been fully elucidated. Here we show that the kinetics of strand displacement in surface-immobilized nanomachines are significantly different to those of the soln. phase reaction, and we attribute this to the effects of intermol. interactions within the DNA layer. We demonstrate that the dynamics of strand displacement can be manipulated by changing strand length, concn. and G/C content. By inserting mismatched bases it is also possible to tune the rates of the constituent displacement processes (toehold-binding and branch migration) independently, and information can be encoded in the time-dependence of the overall reaction. Our findings will facilitate the rational design of surface-immobilized dynamic DNA nanomachines, including computing devices and track-based motors.
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    Broadwater, D. W. B.; Kim, H. D. The Effect of Basepair Mismatch on DNA Strand Displacement. Biophys. J. 2016, 110 (7), 1476– 1484,  DOI: 10.1016/j.bpj.2016.02.027
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    The Effect of Basepair Mismatch on DNA Strand Displacement
    Broadwater, D. W. Bo; Kim, Harold D.
    Biophysical Journal (2016), 110 (7), 1476-1484CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
    DNA strand displacement is a key reaction in DNA homologous recombination and DNA mismatch repair and is also heavily utilized in DNA-based computation and locomotion. Despite its ubiquity in science and engineering, sequence-dependent effects of displacement kinetics have not been extensively characterized. Here, we measured toehold-mediated strand displacement kinetics using single-mol. fluorescence in the presence of a single basepair mismatch. The apparent displacement rate varied significantly when the mismatch was introduced in the invading DNA strand. The rate generally decreased as the mismatch in the invader was encountered earlier in displacement. Our data indicate that a single base pair mismatch in the invader stalls branch migration and displacement occurs via direct dissocn. of the destabilized incumbent strand from the substrate strand. We combined both branch migration and direct dissocn. into a model, which we term the concurrent displacement model, and used the first passage time approach to quant. explain the salient features of the obsd. relationship. We also introduce the concept of splitting probabilities to justify that the concurrent model can be simplified into a three-step sequential model in the presence of an invader mismatch. We expect our model to become a powerful tool to design DNA-based reaction schemes with broad functionality.
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    Li, Q.; Zhao, J.; Liu, L.; Jonchhe, S.; Rizzuto, F. J.; Mandal, S.; He, H.; Wei, S.; Sleiman, H. F.; Mao, H.; Mao, C. A Poly(Thymine)–Melamine Duplex for the Assembly of DNA Nanomaterials. Nat. Mater. 2020, 19 (9), 1012– 1018,  DOI: 10.1038/s41563-020-0728-2
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    A poly(thymine)-melamine duplex for the assembly of DNA nanomaterials
    Li, Qian; Zhao, Jiemin; Liu, Longfei; Jonchhe, Sagun; Rizzuto, Felix J.; Mandal, Shankar; He, Huawei; Wei, Sansen; Sleiman, Hanadi F.; Mao, Hanbin; Mao, Chengde
    Nature Materials (2020), 19 (9), 1012-1018CODEN: NMAACR; ISSN:1476-1122. (Nature Research)
    Abstr.: The diversity of DNA duplex structures is limited by a binary pair of hydrogen-bonded motifs. Here we show that poly(thymine) self-assocs. into antiparallel, right-handed duplexes in the presence of melamine, a small mol. that presents a triplicate set of the hydrogen-bonding face of adenine. X-ray crystallog. shows that in the complex two poly(thymine) strands wrap around a helical column of melamine, which hydrogen bonds to thymine residues on two of its three faces. The mech. strength of the thymine-melamine-thymine triplet surpasses that of adenine-thymine base pairs, which enables a sensitive detection of melamine at 3 pM. The poly(thymine)-melamine duplex is orthogonal to native DNA base pairing and can undergo strand displacement without the need for overhangs. Its incorporation into two-dimensional grids and hybrid DNA-small-mol. polymers highlights the poly(thymine)-melamine duplex as an addnl. tool for DNA nanotechnol.
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    Biosensors employ biol. mols. to recognize the target and utilize output elements which can translate the biorecognition event into elec., optical or mass-sensitive signals to det. the quantities of the target. DNA-based biosensors, as a sub-field to biosensor, utilize DNA strands with short oligonucleotides as probes for target recognition. Although DNA-based biosensors have offered a promising alternative for fast, simple and cheap detection of target mols., there still exist key challenges including poor stability and reproducibility that hinder their competition with the current gold std. for DNA assays. By exploiting the self-recognition properties of DNA mols., researchers have dedicated to make versatile DNA nanostructures in a highly rigid, controllable and functionalized manner, which offers unprecedented opportunities for developing DNA-based biosensors. In this review, we will briefly introduce the recent advances on design and fabrication of static and dynamic DNA nanostructures, and summarize their applications for fabrication and functionalization of DNA-based biosensors.
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    The availability of sensors able to rapidly detect SARS-CoV-2 directly in biol. fluids in a single step would allow performing massive diagnostic testing to track in real time and contain the spread of COVID-19. Motivated by this, here, we developed an electrochem. aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quant. measurement of the SARS-CoV-2 spike (S) protein. First, we demonstrated the ability of the selected aptamer to undergo a binding-induced conformational change in the presence of its target using fluorescence spectroscopy. Then, we engineered the aptamer to work as a bioreceptor in the EAB platform and we demonstrated its sensitivity and specificity. Finally, to demonstrate the clin. potential of the sensor, we tested it directly in biol. fluids (serum and artificial saliva), achieving the rapid (minutes) and single-step detection of the S protein in its clin. range.
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  1. Federica Curti, Simone Fortunati, Wolfgang Knoll, Marco Giannetto, Roberto Corradini, Alessandro Bertucci, Maria Careri. A Folding-Based Electrochemical Aptasensor for the Single-Step Detection of the SARS-CoV-2 Spike Protein. ACS Applied Materials & Interfaces 2022, 14 (17) , 19204-19211. https://doi.org/10.1021/acsami.2c02405
  2. Hanxuan Wang, Ardemis A. Boghossian. Covalent conjugation of proteins onto fluorescent single-walled carbon nanotubes for biological and medical applications. Materials Advances 2023, 4 (3) , 823-834. https://doi.org/10.1039/D2MA00714B
  3. Aqsa Khan, Emily DeVoe, Silvana Andreescu. Carbon-based electrochemical biosensors as diagnostic platforms for connected decentralized healthcare. Sensors & Diagnostics 2023, 171 https://doi.org/10.1039/D2SD00226D
  4. Qihong Ning, Shaoqing Feng, Yuemeng Cheng, Tangan Li, Daxiang Cui, Kan Wang. Point-of-care biochemical assays using electrochemical technologies: approaches, applications, and opportunities. Microchimica Acta 2022, 189 (8) https://doi.org/10.1007/s00604-022-05425-z
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  • Abstract

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    Figure 1

    Figure 1. (a) Schematic illustration of the functionalization of SWCNT-SPEs with amine-modified DNA probes. (b) Current signals obtained using different concentrations of biotinylated DNA probe reactant (mean value ± sd, n = 3, **p < 0.01, ns = nonsignificant) following incubation with alkaline phosphatase–streptavidin conjugates and its enzymatic substrate.

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    Figure 2

    Figure 2. (a) Schematic illustration of the electrode surface treatment with pyrene as a backfilling agent to reduce nonspecific adsorption of DNA strands. MB is the Atto-MB2 redox tag. (b) Nonspecific signal reduction % relative to untreated electrodes when pyrene is used as a backfilling agent at different concentrations of a sample nonspecific DNA strand (mean value ± sd, n = 3). (c) Representative voltammograms obtained when redox-tagged nonspecific DNA (100 nM) was incubated on untreated (black curve), BSA-treated (blue curve) and pyrene-treated DNA-functionalized SWCNT-SPEs (red curve), and (d) the corresponding measured current signals (mean value ± sd, n = 3).

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    Figure 3

    Figure 3. (a) Schematic drawing of the formation of specific DNA duplexes on the CNT electrode surface. MB is the Atto-MB2 redox tag. (b) Representative voltammograms obtained using a redox-tagged full-match DNA (100 nM) and a redox-tagged nonspecific DNA (100 nM), respectively. The difference between the two signals gives the hybridization current specific to the formed duplexes. (c) Hybridization current values obtained using different concentrations of full-match DNA (mean value ± sd, n = 3). (d) Linear fit of normalized hybridization currents for full-match DNA concentrations in the 30–100 nM range. Hybridization currents were normalized with respect to the most intense response recorded at the 100 nM concentration level.

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    Figure 4

    Figure 4. (a) Schematic illustration of a toehold-mediated DNA strand displacement reaction conducted on the surface of SWCNT-SPEs, which can be monitored via amperometric measurements as an invader strand removes a redox-tagged strand near the electrode surface. MB is the Atto-MB2 redox tag. (b) Representative voltammograms recorded in the presence of different concentrations of the invader strand. (c) Relative hybridization current values measured in the presence of different concentrations of the invader strand (mean value ± sd, n = 3).

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    Figure 5

    Figure 5. (a) Schematic drawing of the controlled formation of artificial poly(T)-melamine duplexes on the surface of SWCNT-SPEs. (b) Table reporting the DNA sequences designed for the controlled assembly of poly(T)-melamine duplexes on the electrode surface. (c) Hybridization current values related to the artificial poly(T)-melamine duplexes obtained using 100 nM of 15-nt poly(T) sequences (0GC), 15-nt poly(T) sequences conjugated with 3 G/C bases (3GC), 15-nt poly(T) sequences conjugated with 6 G/C bases (6GC), respectively, in the presence of 1 mM melamine (mean value ± sd, n = 3). (d) Representative voltammograms obtained using 15(T)-3GC-duplex-forming strands (100 nM) in the presence (solid line) and in the absence (dashed line) of melamine (1 mM), respectively. The difference between the two signals is the hybridization current specific to the formed artificial poly(T)-melamine duplexes. (e) Schematic illustration of a strand exchange reaction conducted at the electrode surface, where a poly(A) strand replaces the central melamine units of an initial poly(T)-melamine duplex to form a canonical poly(T)-poly(A) duplex. (f) Representative voltammograms recorded in the presence (blue line) and in the absence (violet line) of a poly(A) sequence reacting with poly(T)-melamine duplexes previously assembled on the electrode surface. (g) Relative hybridization current values obtained upon incubation with a poly(A) invader strand (100 nM), showing that the induced strand exchange reaction is almost quantitative (mean value ± sd, n = 3).

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      Expanding the Scope of Protein-Detecting Electrochemical DNA "Scaffold" Sensors
      Kang, Di; Parolo, Claudio; Sun, Sheng; Ogden, Nathan E.; Dahlquist, Frederick W.; Plaxco, Kevin W.
      ACS Sensors (2018), 3 (7), 1271-1275CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      The ability to measure the levels of diagnostically relevant proteins, such as antibodies, directly at the point of care could significantly impact healthcare. Thus motivated, we explore here the E-DNA "scaffold" sensing platform, a rapid, convenient, single-step means to this end. These sensors comprise a rigid nucleic acid "scaffold" attached via a flexible linker to an electrode and modified on its distal end with a redox reporter and a protein binding "recognition element". The binding of a targeted protein reduces the efficiency with which the redox reporter approaches the electrode, resulting in an easily measured signal change when the sensor is interrogated voltammetrically. Previously we have demonstrated scaffold sensors employing a range of low mol. wt. haptens and linear peptides as their recognition elements. Expanding on this here we have characterized sensors employing much larger recognition elements (up to and including full length proteins) in order to (1) define the range of recognition elements suitable for use in the platform; (2) better characterize the platform's signaling mechanism to aid its design and optimization; and (3) demonstrate the anal. performance of sensors employing full-length proteins as recognition elements. In doing so we have enlarged the range of mol. targets amenable to this rapid and convenient sensing platform.
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    6. 6
      Fan, C.; Plaxco, K. W.; Heeger, A. J. Electrochemical Interrogation of Conformational Changes as a Reagentless Method for the Sequence-Specific Detection of DNA. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (16), 9134– 9137,  DOI: 10.1073/pnas.1633515100
      6
      Electrochemical interrogation of conformational changes as a reagentless method for the sequence-specific detection of DNA
      Fan, Chunhai; Plaxco, Kevin W.; Heeger, Alan J.
      Proceedings of the National Academy of Sciences of the United States of America (2003), 100 (16), 9134-9137CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      We report a strategy for the reagentless transduction of DNA hybridization into a readily detectable electrochem. signal by means of a conformational change analogous to the optical mol. beacon approach. The strategy involves an electroactive, ferrocene-tagged DNA stem-loop structure that self-assembles onto a gold electrode by means of facile gold-thiol chem. Hybridization induces a large conformational change in this surface-confined DNA structure, which in turn significantly alters the electron-transfer tunneling distance between the electrode and the redoxable label. The resulting change in electron transfer efficiency is readily measured by cyclic voltammetry at target DNA concns. as low as 10 pM. In contrast to existing optical approaches, an electrochem. DNA (E-DNA) sensor built on this strategy can detect femtomoles of target DNA without employing cumbersome and expensive optics, light sources, or photodetectors. In contrast to previously reported electrochem. approaches, the E-DNA sensor achieves this impressive sensitivity without the use of exogenous reagents and without sacrificing selectivity or reusability. The E-DNA sensor thus offers the promise of convenient, reusable detection of picomolar DNA.
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    7. 7
      Ye, D.; Zuo, X.; Fan, C. DNA Nanotechnology-Enabled Interfacial Engineering for Biosensor Development. Annu. Rev. Anal. Chem. 2018, 11 (1), 171– 195,  DOI: 10.1146/annurev-anchem-061417-010007
      7
      DNA Nanotechnology-Enabled Interfacial Engineering for Biosensor Development
      Ye, Dekai; Zuo, Xiaolei; Fan, Chunhai
      Annual Review of Analytical Chemistry (2018), 11 (), 171-195CODEN: ARACFU; ISSN:1936-1327. (Annual Reviews)
      A review. Biosensors represent biomimetic anal. tools for addressing increasing needs in medical diagnosis, environmental monitoring, security, and biodefense. Nevertheless, widespread real-world applications of biosensors remain challenging due to limitations of performance, including sensitivity, specificity, speed, and reproducibility. In this review, we present a DNA nanotechnol.-enabled interfacial engineering approach for improving the performance of biosensors. We first introduce the main challenges of the biosensing interfaces, esp. under the context of controlling the DNA interfacial assembly. We then summarize recent progress in DNA nanotechnol. and efforts to harness DNA nanostructures to engineer various biol. interfaces, with a particular focus on the use of framework nucleic acids. We also discuss the implementation of biosensors to detect physiol. relevant nucleic acids, proteins, small mols., ions, and other biomarkers. This review highlights promising applications of DNA nanotechnol. in interfacial engineering for biosensors and related areas.
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    8. 8
      Rossetti, M.; Brannetti, S.; Mocenigo, M.; Marini, B.; Ippodrino, R.; Porchetta, A. Harnessing Effective Molarity to Design an Electrochemical DNA-based Platform for Clinically Relevant Antibody Detection. Angew. Chem., Int. Ed. 2020, 132 (35), 15083– 15088,  DOI: 10.1002/ange.202005124
      There is no corresponding record for this reference.
    9. 9
      Castagna, R.; Bertucci, A.; Prasetyanto, E. A.; Monticelli, M.; Conca, D. V.; Massetti, M.; Sharma, P. P.; Damin, F.; Chiari, M.; De Cola, L.; Bertacco, R. Reactive Microcontact Printing of DNA Probes on (DMA-NAS-MAPS) Copolymer-Coated Substrates for Efficient Hybridization Platforms. Langmuir 2016, 32 (13), 3308– 3313,  DOI: 10.1021/acs.langmuir.5b04669
      9
      Reactive Microcontact Printing of DNA Probes on (DMA-NAS-MAPS) Copolymer-Coated Substrates for Efficient Hybridization Platforms
      Castagna, Rossella; Bertucci, Alessandro; Prasetyanto, Eko Adi; Monticelli, Marco; Conca, Dario Valter; Massetti, Matteo; Sharma, Parikshit Pratim; Damin, Francesco; Chiari, Marcella; De Cola, Luisa; Bertacco, Riccardo
      Langmuir (2016), 32 (13), 3308-3313CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      High-performing hybridization platforms fabricated by reactive microcontact printing of DNA probes are presented. Multishaped PDMS molds are used to covalently bind oligonucleotides over a functional copolymer (DMA-NAS-MAPS) surface. Printed structures with min. width of about 1.5 μm, spaced by 10 μm, are demonstrated, with edge corrugation lower than 300 nm. The quantification of the immobilized surface probes via fluorescence imaging gives a remarkable concn. of 3.3 × 103 oligonucleotides/μm2, almost totally active when used as probes in DNA-DNA hybridization assays. Indeed, fluorescence and at. force microscopy show a 95% efficiency in target binding and uniform DNA hybridization over printed areas.
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    10. 10
      Kogikoski, S.; Paschoalino, W. J.; Cantelli, L.; Silva, W.; Kubota, L. T. Electrochemical Sensing Based on DNA Nanotechnology. TrAC Trends Anal. Chem. 2019, 118, 597– 605,  DOI: 10.1016/j.trac.2019.06.021
      10
      Electrochemical sensing based on DNA nanotechnology
      Kogikoski, Sergio; Paschoalino, Waldemir J.; Cantelli, Lory; Silva, Wilgner; Kubota, Lauro T.
      TrAC, Trends in Analytical Chemistry (2019), 118 (), 597-605CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B.V.)
      A review. Electrochem. sensing is one of the major areas in anal. chem., since it is easy, reliable, and cheap compared to other anal. techniques. In this way, using DNA to develop novel electrochem. sensing devices bring many advantages compared to other biomols. However, the electrochem. properties of DNA are still under discovery. Herein we show three different properties of DNA, which were already studied by electrochem., and that can be further explored: (1) the DNA cond., derived from the base pair stacking enabling DNA to be a mol. wire; (2) DNA computing, derived from the interaction between different DNA sequences enabling the performance of logic to perform anal. operations; and (3) DNA self-assembly, due to base pairing, DNA can form nanostructures that can provide better electrochem. control. Finally, some perspectives for the topic will be discussed, focusing mainly in the interdisciplinary use of DNA nanostructures in electrochem.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlaqurbF&md5=aca18ecb60742f26713563c0bc863fd7
    11. 11
      Lin, M.; Song, P.; Zhou, G.; Zuo, X.; Aldalbahi, A.; Lou, X.; Shi, J.; Fan, C. Electrochemical Detection of Nucleic Acids, Proteins, Small Molecules and Cells Using a DNA-Nanostructure-Based Universal Biosensing Platform. Nat. Protoc. 2016, 11 (7), 1244– 1263,  DOI: 10.1038/nprot.2016.071
      11
      Electrochemical detection of nucleic acids, proteins, small molecules and cells using a DNA-nanostructure-based universal biosensing platform
      Lin, Meihua; Song, Ping; Zhou, Guobao; Zuo, Xiaolei; Aldalbahi, Ali; Lou, Xiaoding; Shi, Jiye; Fan, Chunhai
      Nature Protocols (2016), 11 (7), 1244-1263CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
      The occurrence and prognosis of many complex diseases, such as cancers, is assocd. with the variation of various mols., including DNA at the genetic level, RNA at the regulatory level, proteins at the functional level and small mols. at the metabolic level (defined collectively as multilevel mols.). Thus it is highly desirable to develop a single platform for detecting multilevel biomarkers for early-stage diagnosis. Here we report a protocol on DNA-nanostructure-based programmable engineering of the biomol. recognition interface, which provides a universal electrochem. biosensing platform for the ultrasensitive detection of nucleic acids (DNA/RNA), proteins, small mols. and whole cells. The protocol starts with the synthesis of a series of differentially sized, self-assembled tetrahedral DNA nanostructures (TDNs) with site-specifically modified thiol groups that can be readily anchored on the surface of a gold electrode with high reproducibility. By exploiting the rigid structure, nanoscale addressability and versatile functionality of TDNs, one can tailor the type of biomol. probes appended on individual TDNs for the detection of specific mols. of interest. Target binding occurring on the gold surface patterned with TDNs is quant. translated into electrochem. signals via a coupled enzyme-based catalytic process. This uses a sandwich assay strategy in which biotinylated reporter probes recognize TDN-bound target biomols., which then allow binding of horseradish-peroxidase-conjugated avidin (avidin-HRP). Hydrogen peroxide (H2O2) is then reduced by avidin-HRP in the presence of TMB (3,3',5,5'-tetramethylbenzidine) to generate a quant. electrochem. signal. The time range for the entire protocol is ∼1 d, whereas the detection process takes ∼30 min to 3 h.
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    12. 12
      Saha, U.; Todi, K.; Malhotra, B. D. Emerging DNA-Based Multifunctional Nano-Biomaterials towards Electrochemical Sensing Applications. Nanoscale 2021, 13 (23), 10305– 10319,  DOI: 10.1039/D1NR02409D
      12
      Emerging DNA-based multifunctional nano-biomaterials towards electrochemical sensing applications
      Saha, Udiptya; Todi, Keshav; Malhotra, Bansi D.
      Nanoscale (2021), 13 (23), 10305-10319CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      A review. DNA is known to be ubiquitous in nature as it is the controlling unit for genetic information storage in most living organisms. Lately, there has been a surge in studies relating to the use of DNA as a biomaterial for various biomedical applications such as biosensing, therapeutics, and drug delivery. The role of DNA as a bioreceptor in biosensors has been known for a long time. DNA-based biosensors are gradually evolving into highly sophisticated and sensitive mol. devices. The current realization of DNA-based biosensors embraces the unique structural and functional properties of DNA in the form of a biopolymer. The interesting properties of DNA, such as self-assembly, programmability, catalytic activity, dynamic behavior, and precise mol. recognition, have led to the emergence of innovative DNA assembly based electrochem. biosensors. This review article aims to cover the recent progress in the field of DNA-based electrochem. (EC) biosensors. It commences with an introduction to electrochem. biosensors and elucidates the advantages of integrating DNA-based materials into them. Besides this, we discuss the principles of EC biosensors based on different types of DNA-based materials. The article concludes by highlighting the outlook and importance of this interesting field for biomedical developments.
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    13. 13
      Das, J.; Ivanov, I.; Montermini, L.; Rak, J.; Sargent, E. H.; Kelley, S. O. An Electrochemical Clamp Assay for Direct, Rapid Analysis of Circulating Nucleic Acids in Serum. Nat. Chem. 2015, 7 (7), 569– 575,  DOI: 10.1038/nchem.2270
      13
      An electrochemical clamp assay for direct, rapid analysis of circulating nucleic acids in serum
      Das, Jagotamoy; Ivanov, Ivaylo; Montermini, Laura; Rak, Janusz; Sargent, Edward H.; Kelley, Shana O.
      Nature Chemistry (2015), 7 (7), 569-575CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The anal. of cell-free nucleic acids (cfNAs), which are present at significant levels in the blood of cancer patients, can reveal the mutational spectrum of a tumor without the need for invasive sampling of the tissue. However, this requires differentiation between the nucleic acids that originate from healthy cells and the mutated sequences shed by tumor cells. Here we report an electrochem. clamp assay that directly detects mutated sequences in patient serum. This is the first successful detection of cfNAs without the need for enzymic amplification, a step that normally requires extensive sample processing and is prone to interference. The new chip-based assay reads out the presence of mutations within 15 min using a collection of oligonucleotides that sequester closely related sequences in soln., and thus allow only the mutated sequence to bind to a chip-based sensor. We demonstrate excellent levels of sensitivity and specificity and show that the clamp assay accurately detects mutated sequences in a collection of samples taken from lung cancer and melanoma patients.
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    14. 14
      Gasparac, R.; Taft, B. J.; Lapierre-Devlin, M. A.; Lazareck, A. D.; Xu, J. M.; Kelley, S. O. Ultrasensitive Electrocatalytic DNA Detection at Two- and Three-Dimensional Nanoelectrodes. J. Am. Chem. Soc. 2004, 126 (39), 12270– 12271,  DOI: 10.1021/ja0458221
      14
      Ultrasensitive Electrocatalytic DNA Detection at Two- and Three-Dimensional Nanoelectrodes
      Gasparac, Rahela; Taft, Bradford J.; Lapierre-Devlin, Melissa A.; Lazareck, Adam D.; Xu, Jimmy M.; Kelley, Shana O.
      Journal of the American Chemical Society (2004), 126 (39), 12270-12271CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Electrochem. DNA detection systems are an attractive approach to the development of multiplexed, high-throughput DNA anal. systems for clin. and research applications. We have engineered a new class of nanoelectrode ensembles (NEEs) that constitute a useful platform for biomol. electrochem. sensing. High-sensitivity DNA detection was achieved at oligonucleotide-functionalized NEEs using a label-free electrocatalytic assay. Attomole-levels of DNA were detected using the NEEs, validating the promise of nanoarchitectures for ultrasensitive biosensing.
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    15. 15
      Pheeney, C. G.; Barton, J. K. DNA Electrochemistry with Tethered Methylene Blue. Langmuir 2012, 28 (17), 7063– 7070,  DOI: 10.1021/la300566x
      15
      DNA Electrochemistry with Tethered Methylene Blue
      Pheeney, Catrina G.; Barton, Jacqueline K.
      Langmuir (2012), 28 (17), 7063-7070CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Methylene blue (MB'), covalently attached to DNA through a flexible C12 alkyl linker, provides a sensitive redox reporter in DNA electrochem. measurements. Tethered, intercalated MB' is reduced through DNA-mediated charge transport; the incorporation of a single base mismatch at position 3, 10, or 14 of a 17-mer causes an attenuation of the signal to 62 ± 3% of the well-matched DNA, irresp. of position in the duplex. The redox signal intensity for MB'-DNA is found to be least 3-fold larger than that of Nile blue (NB)-DNA, indicating that MB' is even more strongly coupled to the π-stack. The signal attenuation due to an intervening mismatch does, however, depend on DNA film d. and the backfilling agent used to passivate the surface. These results highlight two mechanisms for redn. of MB' on the DNA-modified electrode: redn. mediated by the DNA base pair stack and direct surface redn. of MB' at the electrode. These two mechanisms are distinguished by their rates of electron transfer that differ by 20-fold. The extent of direct redn. at the surface can be controlled by assembly and buffer conditions.
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    16. 16
      Muren, N. B.; Barton, J. K. Electrochemical Assay for the Signal-On Detection of Human DNA Methyltransferase Activity. J. Am. Chem. Soc. 2013, 135 (44), 16632– 16640,  DOI: 10.1021/ja4085918
      16
      Electrochemical Assay for the Signal-On Detection of Human DNA Methyltransferase Activity
      Muren, Natalie B.; Barton, Jacqueline K.
      Journal of the American Chemical Society (2013), 135 (44), 16632-16640CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Strategies to detect human DNA methyltransferases are needed, given that aberrant methylation by these enzymes is assocd. with cancer initiation and progression. Here we describe a nonradioactive, antibody-free, electrochem. assay in which methyltransferase activity on DNA-modified electrodes confers protection from restriction for signal-on detection. We implement this assay with a multiplexed chip platform and show robust detection of both bacterial (SssI) and human (Dnmt1) methyltransferase activity. Essential to work with human methyltransferases, our unique assay design allows activity measurements on both unmethylated and hemimethylated DNA substrates. We validate this assay by comparison with a conventional radioactive method. The advantages of electrochem. over radioactivity and fluorescence make this assay an accessible and promising new approach for the sensitive, label-free detection of human methyltransferase activity.
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    17. 17
      Dubuisson, E.; Yang, Z.; Loh, K. P. Optimizing Label-Free DNA Electrical Detection on Graphene Platform. Anal. Chem. 2011, 83 (7), 2452– 2460,  DOI: 10.1021/ac102431d
      17
      Optimizing Label-Free DNA Electrical Detection on Graphene Platform
      Dubuisson, Emilie; Yang, Zhiyong; Loh, Kian Ping
      Analytical Chemistry (Washington, DC, United States) (2011), 83 (7), 2452-2460CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The anodized epitaxial graphene (EG) electrode demonstrates a high level of performance for electrochem. impedance as well as differential pulse voltammetry detection of immobilized DNA and free DNA, resp., at solid-liq. interfaces. On the anodized EG surface, because of the presence of oxygen functionalities as well as π conjugated domains, the anchoring of the DNA probe can be achieved by either covalent grafting or noncovalent π-π stacking readily. The effect of different binding modes on the sensitivity of the impedimetric sensing was investigated. Equivalent circuit modeling shows that the sensitivity of EG to DNA hybridization is controlled by changes in the resistance of the mol. layer as well as the space charge layer. The linear dynamic detection range of EG for DNA oligonucleotides is in the range of 5.0 × 10-14 to 1 × 10-6 M. In addn., with the use of differential pulse voltammetry, single stranded DNA, fully complementary DNA, as well as single nucleotide polymorphisms can be differentiated on anodized EG by monitoring the oxidn. signals of individual nucleotide bases.
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    18. 18
      Campuzano, S.; Yáñez-Sedeño, P.; Pingarrón, J. M. Tailoring Sensitivity in Electrochemical Nucleic Acid Hybridization Biosensing: Role of Surface Chemistry and Labeling Strategies. ChemElectroChem. 2019, 6 (1), 60– 72,  DOI: 10.1002/celc.201800667
      18
      Tailoring Sensitivity in Electrochemical Nucleic Acid Hybridization Biosensing: Role of Surface Chemistry and Labeling Strategies
      Campuzano, Susana; Yanez-Sedeno, Paloma; Pingarron, Jose Manuel
      ChemElectroChem (2019), 6 (1), 60-72CODEN: CHEMRA; ISSN:2196-0216. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Electrochem. nucleic acid hybridization biosensors have become a mainstay to detect DNA or RNA targets of interest in clin. diagnostics, environmental monitoring and food quality control. Despite the great progress they demonstrated during the last years, there is a const. demand to improve their performance, mainly in terms of sensitivity, simplicity of protocols and easy implementation in routine and decentralized detns. Within this context, the tremendous possibilities offered by both, a judicious interfacing of the electrode surface, and the use of innovative labeling strategies not requiring nanomaterials or nucleic acid amplification, is discussed critically in this review.
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    19. 19
      Michaels, P.; Alam, M. T.; Ciampi, S.; Rouesnel, W.; Parker, S. G.; Choudhury, M. H.; Gooding, J. J. A Robust DNA Interface on a Silicon Electrode. Chem. Commun. 2014, 50 (58), 7878– 7880,  DOI: 10.1039/C4CC03418J
      19
      A robust DNA interface on a silicon electrode
      Michaels, Pauline; Alam, Muhammad Tanzirul; Ciampi, Simone; Rouesnel, William; Parker, Stephen G.; Choudhury, Moinul H.; Gooding, J. Justin
      Chemical Communications (Cambridge, United Kingdom) (2014), 50 (58), 7878-7880CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Two different interfaces prepd. via UV-hydrosilylation of undecylenic acid and 1,8-nonadiyne on silicon(111) have been explored to develop a robust electrochem. DNA sensor. Electrodes modified with undecylenic acid stably immobilize DNA but could not resist the growth of insulating oxides, whereas 1,8-nonadiyne modified electrodes satisfy both requirements.
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    20. 20
      Ricci, F.; Zari, N.; Caprio, F.; Recine, S.; Amine, A.; Moscone, D.; Palleschi, G.; Plaxco, K. W. Surface Chemistry Effects on the Performance of an Electrochemical DNA Sensor. Bioelectrochemistry 2009, 76 (1–2), 208– 213,  DOI: 10.1016/j.bioelechem.2009.03.007
      20
      Surface chemistry effects on the performance of an electrochemical DNA sensor
      Ricci, Francesco; Zari, Nadia; Caprio, Felice; Recine, Simona; Amine, Aziz; Moscone, Danila; Palleschi, Giuseppe; Plaxco, Kevin W.
      Bioelectrochemistry (2009), 76 (1-2), 208-213CODEN: BIOEFK; ISSN:1567-5394. (Elsevier B.V.)
      E-DNA sensors are a reagentless, electrochem. oligonucleotide sensing platform based on a redox-tag modified, electrode-bound probe DNA. Because E-DNA signaling is linked to hybridization-linked changes in the dynamics of this probe, sensor performance is likely dependent on the nature of the self-assembled monolayer coating the electrode. The authors have investigated this question by characterizing the gain, specificity, response time and shelf-life of E-DNA sensors fabricated using a range of co-adsorbates, including both charged and neutral alkane thiols. The authors find that, among the thiols tested, the pos. charged cysteamine gives rise to the largest and most rapid response to target and leads to significantly improved storage stability. The best mismatch specificity, however, is achieved with mercaptoethanesulfonic and mercaptoundecanol, presumably due to the destabilizing effects of, resp., the neg. charge and steric bulk of these co-adsorbates. These results demonstrate that a careful choice of co-adsorbate chem. can lead to significant improvements in the performance of this broad class of electrochem. DNA sensors.
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    21. 21
      Wang, J.; Musameh, M. Carbon Nanotube Screen-Printed Electrochemical Sensors. Analyst 2004, 129 (1), 1,  DOI: 10.1039/b313431h
      21
      Carbon nanotube screen-printed electrochemical sensors
      Wang, Joseph; Musameh, Mustafa
      Analyst (Cambridge, United Kingdom) (2004), 129 (1), 1-2CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      The fabrication, and evaluation of C-nanotube (CNT)-derived screen-printed (SP) electrochem. sensors based on a CNT ink are reported. The fabricated CNT strips combine the attractive advantages of CNT materials and disposable screen-printed electrodes. Such thick-film CNT sensors have a well-defined appearance, are mech. stable, and exhibit high electrochem. reactivity.
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    22. 22
      Rasheed, P. A.; Sandhyarani, N. Carbon Nanostructures as Immobilization Platform for DNA: A Review on Current Progress in Electrochemical DNA Sensors. Biosens. Bioelectron. 2017, 97, 226– 237,  DOI: 10.1016/j.bios.2017.06.001
      22
      Carbon nanostructures as immobilization platform for DNA: A review on current progress in electrochemical DNA sensors
      Rasheed P Abdul; Sandhyarani N
      Biosensors & bioelectronics (2017), 97 (), 226-237 ISSN:.
      Development of a sensitive, specific and cost-effective DNA detection method is motivated by increasing demand for the early stage diagnosis of genetic diseases. Recent developments in the design and fabrication of efficient sensor platforms based on nanostructures make the highly sensitive sensors which could indicate very low detection limit to the level of few molecules, a realistic possibility. Electrochemical detection methods are widely used in DNA diagnostics as it provide simple, accurate and inexpensive platform for DNA detection. In addition, the electrochemical DNA sensors provide direct electronic signal without the use of expensive signal transduction equipment and facilitates the immobilization of single stranded DNA (ssDNA) probe sequences on a wide variety of electrode substrates. It has been found that a range of nanomaterials such as metal nanoparticles (MNPs), carbon based nanomaterials, quantum dots (QDs), magnetic nanoparticles and polymeric NPs have been introduced in the sensor design to enhance the sensing performance of electrochemical DNA sensor. In this review, we discuss recent progress in the design and fabrication of efficient electrochemical genosensors based on carbon nanostructures such as carbon nanotubes, graphene, graphene oxide and nanodiamonds.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnntVertA%253D%253D&md5=310556546fcfd2d51f6834fc37f44f89
    23. 23
      Giannetto, M.; Bianchi, M. V.; Mattarozzi, M.; Careri, M. Competitive Amperometric Immunosensor for Determination of P53 Protein in Urine with Carbon Nanotubes/Gold Nanoparticles Screen-Printed Electrodes: A Potential Rapid and Noninvasive Screening Tool for Early Diagnosis of Urinary Tract Carcinoma. Anal. Chim. Acta 2017, 991, 133– 141,  DOI: 10.1016/j.aca.2017.09.005
      23
      Competitive amperometric immunosensor for determination of p53 protein in urine with carbon nanotubes/gold nanoparticles screen-printed electrodes: A potential rapid and noninvasive screening tool for early diagnosis of urinary tract carcinoma
      Giannetto, Marco; Bianchi, Maria Vittoria; Mattarozzi, Monica; Careri, Maria
      Analytica Chimica Acta (2017), 991 (), 133-141CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
      Since p53 protein has become recognized biomarker for both diagnostic and therapeutic purposes in oncol. diseases with particular relevance for bladder cancer, it is highly desirable to search for a novel sensing tool for detecting the patient's p53 level at the early stage. Here the authors report the first study on the development and validation of a novel disposable competitive amperometric immunosensor for detn. of p53 protein at subnanomolar levels, based on p53 immobilization on gold nanoparticles/carbon nanotubes modified screen-printed carbon electrodes. The assay protocol requires the use of single anti-p53 mouse monoclonal antibody (DO-7 clone), able to recognize both wild-type and mutant p53. The developed immunosensor as well as the protocol of the electrochem. immunoassay were optimized by an exptl. design procedure to assess the suitability of the device to be validated and applied for the detn. of p53 in untreated and undiluted urine samples. The developed competitive immunodevice was able to achieve wide linear range detection of wild-type p53 from 20 pM to 10 nM with a low detection limit of 14 pM in synthetic urine samples, suggesting the sensor's capability of working in a complex sample matrix. The excellent performance results also in terms of selectivity, trueness and precision, coupled with the advantages of an easy prepn. and low-cost assay in contrast to other methods which require very complex, time-consuming and costly nanostructured architectures, makes the developed competitive immunosensor an anal. robust diagnostic tool, valuable for implementation of screening and follow-up programs in patients with urol. malignancies.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFWgurfM&md5=666b102956dee49b9df7e35a6294ac3b
    24. 24
      Fortunati, S.; Rozzi, A.; Curti, F.; Giannetto, M.; Corradini, R.; Careri, M. Single-Walled Carbon Nanotubes as Enhancing Substrates for PNA-Based Amperometric Genosensors. Sensors 2019, 19 (3), 588,  DOI: 10.3390/s19030588
      24
      Single-walled carbon nanotubes as enhancing substrates for PNA-based amperometric genosensors
      Fortunati, Simone; Rozzi, Andrea; Curti, Federica; Giannetto, Marco; Corradini, Roberto; Careri, Maria
      Sensors (2019), 19 (3), 588/1-588/9CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)
      A new amperometric sandwich-format genosensor has been implemented on single-walled carbon nanotubes screen printed electrodes (SWCNT-SPEs) and compared in terms of performance with analogous genoassays developed using the same methodol. on non-nanostructured glassy carbon platforms (GC-SPE). The working principle of the genosensors is based on the covalent immobilization of Peptide Nucleic Acid (PNA) capture probes (CP) on the electrode surface, carried out through the carboxylic functions present on SWCNT-SPEs (carboxylated SWCNT) or electrochem. induced on GC-SPEs. The sequence of the CP was complementary to a 20-mer portion of the target DNA; a second biotin-tagged PNA signalling probe (SP), with sequence complementary to a different contiguous portion of the target DNA, was used to obtain a sandwich hybrid with an Alk. Phosphatase-streptavidin conjugate (ALP-Strp). Comparison of the responses obtained from the SWCNT-SPEs with those produced from the non-nanostructured substrates evidenced the remarkable enhancement effect given by the nanostructured electrode platforms, achieved both in terms of loading capability of PNA probes and amplification of the electron transfer phenomena exploited for the signal transduction, giving rise to more than four-fold higher sensitivity when using SWCNT-SPEs. The nanostructured substrate allowed to reach limit of detection (LOD) of 71 pM and limit of quantitation (LOQ) of 256 pM, while the corresponding values obtained with GC-SPEs were 430 pM and 1.43 nM, resp.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFCisrzK&md5=5e08f6dffd037702b16d4fadfc645565
    25. 25
      Hu, C.; Zhang, Y.; Bao, G.; Zhang, Y.; Liu, M.; Wang, Z. L. DNA Functionalized Single-Walled Carbon Nanotubes for Electrochemical Detection. J. Phys. Chem. B 2005, 109 (43), 20072– 20076,  DOI: 10.1021/jp0550457
      25
      DNA Functionalized Single-Walled Carbon Nanotubes for Electrochemical Detection
      Hu, Chenguo; Zhang, Yiyi; Bao, Gang; Zhang, Yuelan; Liu, Meilin; Wang, Zhong Lin
      Journal of Physical Chemistry B (2005), 109 (43), 20072-20076CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      Single-walled carbon nanotubes (SWNTs) were effectively dispersed and functionalized by wrapping with single-stranded DNA (ssDNA). The ssDNA-SWNTs attach strongly on glass substrate and easily form a uniform film, making it possible for electrochem. anal. and sensing. The film was fabricated into a working electrode, which exhibited good electrochem. voltammetric properties, such as flat and wide potential window, well-defined quasi-reversible voltammetric responses, and quick electron transfer for a Fe(CN)63-/Fe(CN)64 system, indicating that the ssDNA-SWNTs film should be a good anal. electrode for electrochem. detection or sensing. This was demonstrated by highly selective and sensitive detection of a low concn. of dopamine in the presence of excess ascorbic acid.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVKmt7fN&md5=7db5c3b5167b806974f928048f113efc
    26. 26
      Zhang, X.; Jiao, K.; Liu, S.; Hu, Y. Readily Reusable Electrochemical DNA Hybridization Biosensor Based on the Interaction of DNA with Single-Walled Carbon Nanotubes. Anal. Chem. 2009, 81 (15), 6006– 6012,  DOI: 10.1021/ac802026j
      26
      Readily reusable electrochemical DNA hybridization biosensor based on the interaction of DNA with single-walled carbon nanotubes
      Zhang, Xuzhi; Jiao, Kui; Liu, Shufeng; Hu, Yuwei
      Analytical Chemistry (Washington, DC, United States) (2009), 81 (15), 6006-6012CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Carboxylic group-functionalized single-walled carbon nanotubes (SWNTs) were assembled vertically on the glassy carbon electrode using ethylenediamine as linking agent to fabricate an aligned electrode (SWNTE). Single-stranded DNA (ssDNA) wrapped around the SWNTs to form ssDNA-wrapped SWNTE structures based on the interaction between ssDNA and SWNT. A sensitive differential pulse voltammetric (DPV) response was obtained at the ssDNA-wrapped SWNTE owing to the electrooxidn. of guanine bases. Double-stranded DNA (dsDNA) was formed when ssDNA on the ssDNA-wrapped SWNTE was hybridized with complementary ssDNA (cDNA). The dsDNA was removed from the SWNTs by undergoing a process of preconditioning at -0.6 V. Consequentially, the DPV response of guanine bases decreased. The used SWNTE could be renewed easily via ultrasonically rinsing. On the basis of this mechanism, a label-free and readily reusable electrochem. DNA hybridization biosensor was designed by directly monitoring the current change of guanine bases. Under optimum conditions, the plot of the measurement signal of guanine bases vs. the cDNA concns. was a good straight line in the range of 40-110 nM with a detection limit of 20 nM (3s). The biosensor can be switched to detect different target DNAs easily.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvVKqs74%253D&md5=05fb2dd8ddcf98efdea46900f002dda6
    27. 27
      Ye, Y.; Ju, H. Rapid Detection of SsDNA and RNA Using Multi-Walled Carbon Nanotubes Modified Screen-Printed Carbon Electrode. Biosens. Bioelectron. 2005, 21 (5), 735– 741,  DOI: 10.1016/j.bios.2005.01.004
      27
      Rapid detection of ssDNA and RNA using multi-walled carbon nanotubes modified screen-printed carbon electrode
      Ye, Yongkang; Ju, Huangxian
      Biosensors & Bioelectronics (2005), 21 (5), 735-741CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      A method for rapid sensitive detection of DNA or RNA was designed using a composite screen-printed carbon electrode modified with multi-walled carbon nanotubes (MWNTs). MWNTs showed catalytic characteristics for the direct electrochem. oxidn. of guanine or adenine residues of single strand DNA (ssDNA) and adenine residues of RNA, leading to indicator-free detection of ssDNA and RNA concns. With an accumulation time of 5 min, the proposed method could be used for detection of calf thymus ssDNA ranging from 17.0 to 345 μg mL-1 with a detection limit of 2.0 μg ml-1 at 3σ and yeast tRNA ranging from 8.2 μg mL-1 to 4.1 mg mL-1. AC impedance was employed to characterize the surface of modified electrodes. The advantages of convenient fabrication, low-cost detection, short anal. time and combination with nanotechnol. for increasing the sensitivity made the subject worthy of special emphasis in the research programs and sources of new com. products.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFCjsLjN&md5=319f6c28a4c5dd014a73a07dcf5b2226
    28. 28
      Jiang, H.; Lee, E.-C. Highly Selective, Reusable Electrochemical Impedimetric DNA Sensors Based on Carbon Nanotube/Polymer Composite Electrode without Surface Modification. Biosens. Bioelectron. 2018, 118, 16– 22,  DOI: 10.1016/j.bios.2018.07.037
      28
      Highly selective, reusable electrochemical impedimetric DNA sensors based on carbon nanotube/polymer composite electrode without surface modification
      Jiang, Huaide; Lee, Eun-Cheol
      Biosensors & Bioelectronics (2018), 118 (), 16-22CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      We fabricated a composite of multi-walled carbon nanotube and polydimethylsiloxane and utilized it as an electrode for DNA sensing using electrochem. impedance spectroscopy. Without any surface modification or probe immobilization, often necessary for other electrodes, this electrode also acts as a recognition layer for DNA via p-p interactions between the multi-walled carbon nanotube and DNA. This electrode is easily reusable via a simple cleansing process, because there are no covalently bonded adsorbates on the electrode. Compared to previous DNA detection based on differential pulse voltammetry using a similar electrode, the measurement time was reduced from 1h to less than 30min, and the limit of detection (25pM) was reduced by a factor of more than five. In addn., our system can detect the single-base mismatch between the target and probe. Our results indicate that electrochem. impedance spectroscopy is promising for utilizing the multi-walled carbon nanotube and polydimethylsiloxane electrode as a DNA sensor.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVSms73M&md5=be3cff4f5504e84fc02651a5c6732320
    29. 29
      Weber, J. E.; Pillai, S.; Ram, M. K.; Kumar, A.; Singh, S. R. Electrochemical Impedance-Based DNA Sensor Using a Modified Single Walled Carbon Nanotube Electrode. Mater. Sci. Eng., C 2011, 31 (5), 821– 825,  DOI: 10.1016/j.msec.2010.12.009
      29
      Electrochemical impedance-based DNA sensor using a modified single walled carbon nanotube electrode
      Weber, Jessica E.; Pillai, Shreekumar; Ram, Manoj Kumar; Kumar, Ashok; Singh, Shree R.
      Materials Science & Engineering, C: Materials for Biological Applications (2011), 31 (5), 821-825CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
      Carbon nanotubes have become promising functional materials for the development of advanced electrochem. biosensors with novel features which could promote electron-transfer with various redox active biomols. This paper presents the detection of Salmonella enterica serovar Typhimurium using chem. modified single walled carbon nanotubes (SWNTs) with single stranded DNA (ssDNA) on a polished glassy carbon electrode. Hybridization with the corresponding complementary ssDNA has shown a shift in the impedance studies due to a higher charge transfer in ssDNA. The developed biosensor has revealed an excellent specificity for the appropriate targeted DNA strand. The methodologies to prep. and functionalize the electrode could be adopted in the development of DNA hybridization biosensor.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsFaju7k%253D&md5=f412cf2670888b7ce80aa141b888cef5
    30. 30
      Bonanni, A.; Esplandiu, M. J.; del Valle, M. Impedimetric Genosensors Employing COOH-Modified Carbon Nanotube Screen-Printed Electrodes. Biosens. Bioelectron. 2009, 24 (9), 2885– 2891,  DOI: 10.1016/j.bios.2009.02.023
      30
      Impedimetric genosensors employing COOH-modified carbon nanotube screen-printed electrodes
      Bonanni, A.; Esplandiu, M. J.; del Valle, M.
      Biosensors & Bioelectronics (2009), 24 (9), 2885-2891CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      Screen-printed electrodes modified with carboxyl functionalized multi-walled carbon nanotubes were used as platforms for impedimetric genosensing of oligonucleotide sequences specific for transgenic insect resistant Bt maize. After covalent immobilization of aminated DNA probe using carbodiimide chem., the impedance measurement was performed in a soln. contg. the redox marker ferrocyanide/ferricyanide. A complementary oligomer (target) was then added, its hybridization was promoted and the measurement performed as before. The change of interfacial charge transfer resistance between the soln. and the electrode surface, experimented by the redox marker at the applied potential, was recorded to confirm the hybrid formation. Non-complementary DNA sequences contg. a different no. of base mismatches were also employed in the expts. in order to test specificity. A signal amplification protocol was then performed, using a biotinylated complementary target to capture streptavidin modified gold nanoparticles, thus increasing the final impedimetric signal (LOD improved from 72 to 22 fmol, maintaining a good reproducibility, in fact RSD < 12.8% in all examd. cases). In order to visualize the presence and distribution of gold nanoparticles, a silver enhancement treatment was applied to electrodes already modified with DNA-nanoparticles conjugate, allowing direct observation by SEM.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvVWgsLs%253D&md5=3a21db0844b7746900635e85a07c6dd9
    31. 31
      Li, C.; Karadeniz, H.; Canavar, E.; Erdem, A. Electrochemical Sensing of Label Free DNA Hybridization Related to Breast Cancer 1 Gene at Disposable Sensor Platforms Modified with Single Walled Carbon Nanotubes. Electrochim. Acta 2012, 82, 137– 142,  DOI: 10.1016/j.electacta.2012.05.057
      31
      Electrochemical sensing of label free DNA hybridization related to breast cancer 1 gene at disposable sensor platforms modified with single walled carbon nanotubes
      Li, Chen-zhong; Karadeniz, Hakan; Canavar, Ece; Erdem, Arzum
      Electrochimica Acta (2012), 82 (), 137-142CODEN: ELCAAV; ISSN:0013-4686. (Elsevier Ltd.)
      The electrochem. monitoring of DNA hybridization related to specific sequences on breast cancer 1 (BRCA1) DNA by using single-walled C nanotube (SWCNT) based screen printed graphite electrodes (SPEs) was performed. After the microscopic characterization of SWCNT-SPE, the optimization of assay was studied. The development of screen printing process combined with nanomaterial based disposable sensor technol. with sensitivity, selectivity and reproducibility, has a great opportunity for DNA detection using differential pulse voltammetry (DPV) by measuring the guanine oxidn. signal obsd. at +1.00 V in the presence of DNA hybridization between BRCA1 probe and its complementary target. The detection limit estd. for signal to noise ratio = 3 corresponds to 378.52 nM target concn. in the 40 μL samples. The voltammetric results on BRCA1 DNA hybridization were also complemented with electrochem. impedance spectroscopy (EIS).
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlCqtrbE&md5=9302fc318d6fff9962d5c4be8b6be5ed
    32. 32
      Karadeniz, H.; Erdem, A.; Caliskan, A. Electrochemical Monitoring of DNA Hybridization by Multiwalled Carbon Nanotube Based Screen Printed Electrodes. Electroanalysis 2008, 20 (17), 1932– 1938,  DOI: 10.1002/elan.200804270
      32
      Electrochemical monitoring of DNA hybridization by multiwalled carbon nanotube based screen printed electrodes
      Karadeniz, Hakan; Erdem, Arzum; Caliskan, Ayfer
      Electroanalysis (2008), 20 (17), 1932-1938CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The application of multiwalled carbon nanotube (MWCNT) based screen printed graphite electrodes (SPEs) was explored in this study for the electrochem. monitoring of DNA hybridization related to specific sequences on Hepatitis B virus (HBV) DNA. After the microscopic characterization of bare MWCNT-SPEs and DNA immobilized ones was performed, the optimization of assay has been studied. The development of screen printing process combined with nanomaterial based disposable sensor technol. leads herein a great opportunity for DNA detection using differential pulse voltammetry (DPV) by measuring the guanine oxidn. signal obsd. at +1.00 V in the presence of DNA hybridization between HBV probe and its complementary, target. The detection limit estd. for signal to noise ratios = 3 corresponds to 96.33 nM target concn. in the 40 μL samples. The advantages of carbon nanotube based screen printed electrode used for electrochem. monitoring of DNA hybridization are discussed with sensitivity, selectivity and reproducibility in comparison with previous nanomaterial based electrochem. transducers developed for DNA or other biomol. recognitions.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2gsbfJ&md5=35ae9dae77ceab40a2cb5453012f6aeb
    33. 33
      Cai, H.; Cao, X.; Jiang, Y.; He, P.; Fang, Y. Carbon Nanotube-Enhanced Electrochemical DNA Biosensor for DNA Hybridization Detection. Anal. Bioanal. Chem. 2003, 375 (2), 287– 293,  DOI: 10.1007/s00216-002-1652-9
      33
      Carbon nanotube-enhanced electrochemical DNA biosensor for DNA hybridization detection
      Cai, Hong; Cao, Xuni; Jiang, Ying; He, Pingang; Fang, Yuzhi
      Analytical and Bioanalytical Chemistry (2003), 375 (2), 287-293CODEN: ABCNBP; ISSN:1618-2642. (Springer-Verlag)
      A novel and sensitive electrochem. DNA biosensor based on multi-walled carbon nanotubes functionalized with a carboxylic acid group (MWNTs-COOH) for covalent DNA immobilization and enhanced hybridization detection is described. The MWNTs-COOH-modified glassy carbon electrode (GCE) was fabricated and oligonucleotides with the 5'-amino group were covalently bonded to the carboxyl group of carbon nanotubes. The hybridization reaction on the electrode was monitored by differential pulse voltammetry (DPV) anal. using an electroactive intercalator daunomycin as an indicator. Compared with previous DNA sensors with oligonucleotides directly incorporated on carbon electrodes, this carbon nanotube-based assay with its large surface area and good charge-transport characteristics dramatically increased DNA attachment quantity and complementary DNA detection sensitivity. This is the first application of carbon nanotubes to the fabrication of an electrochem. DNA biosensor with a favorable performance for the rapid detection of specific hybridization.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXosVOntA%253D%253D&md5=9baba14f6847b65d390315892dfa9a7f
    34. 34
      Erdem, A.; Papakonstantinou, P.; Murphy, H. Direct DNA Hybridization at Disposable Graphite Electrodes Modified with Carbon Nanotubes. Anal. Chem. 2006, 78 (18), 6656– 6659,  DOI: 10.1021/ac060202z
      34
      Direct DNA Hybridization at Disposable Graphite Electrodes Modified with Carbon Nanotubes
      Erdem, Arzum; Papakonstantinou, Pagona; Murphy, Hayley
      Analytical Chemistry (2006), 78 (18), 6656-6659CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The performance of glassy carbon (GCE) and graphite pencil electrodes (PGE) modified with multiwalled carbon nanotubes (CNTs) are compared, based on the direct electrochem. detection of nucleic acids. This is accomplished by monitoring the differential pulse voltammetry changes of the guanine signal. CNT-modified PGE compares favorably to that of the commonly used CNT-modified GCE owing to the intrinsic improved performance of the supporting PGE. The better intrinsic characteristics of the PGE are related to its composite structure and higher level of porosity compared to GCE. The performance characteristics of the direct DNA hybridization on the disposable CNT-modified PGE are studied in terms of optimum anal. conditions such as probe concn., target concn., hybridization time, and selectivity. The new DNA biosensor described here has shown some important advantages such being inexpensive, sensitive, selective, and able to generate reproducible results using a simple and direct electrochem. protocol.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnvFOgtbk%253D&md5=9a0133ae4a5847aec802c7539e13e95d
    35. 35
      Fortunati, S.; Rozzi, A.; Curti, F.; Giannetto, M.; Corradini, R.; Careri, M. Novel Amperometric Genosensor Based on Peptide Nucleic Acid (PNA) Probes Immobilized on Carbon Nanotubes-Screen Printed Electrodes for the Determination of Trace Levels of Non-Amplified DNA in Genetically Modified (GM) Soy. Biosens. Bioelectron. 2019, 129, 7– 14,  DOI: 10.1016/j.bios.2019.01.020
      35
      Novel amperometric genosensor based on peptide nucleic acid (PNA) probes immobilized on carbon nanotubes-screen printed electrodes for the determination of trace levels of non-amplified DNA in genetically modified (GM) soy
      Fortunati, Simone; Rozzi, Andrea; Curti, Federica; Giannetto, Marco; Corradini, Roberto; Careri, Maria
      Biosensors & Bioelectronics (2019), 129 (), 7-14CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      A novel amperometric genosensor based on PNA probes covalently bound on the surface of Single Walled Carbon Nanotubes - Screen Printed Electrodes (SWCNT-SPEs) was developed and validated in samples of non-amplified genomic DNA extd. from genetically modified (GM)-Soy. The sandwich assay is based on a first recognition of a 20-mer portion of the target DNA by a complementary PNA Capture Probe (CP) and a second hybridization with a PNA Signalling Probe (SP), with a complementary sequence to a different portion of the target DNA. The SP was labeled with biotin to measure current signal by means of a final incubation of an Alk. Phosphatase-streptavidin conjugate (ALP-Strp). The electrochem. detection was carried out using hydroquinone diphosphate (HQDP) as enzymic substrate. The genoassay provided a linear range from 250 pM to 2.5 nM, LOD of 64 pM and LOQ of 215 pM Excellent selectivity towards one base mismatch (1-MM) or scrambled (SCR) sequences was obtained. A simple protocol for extn. and anal. of non-amplified soybean genomic DNA without sample treatment was developed and validated. Our study provides insight into how the outstanding recognition efficiency of PNAs can be combined with the unique properties of CNTs in terms of signal response enhancement for direct detection of genomic DNA samples at the level of interest without previous amplification.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1artrw%253D&md5=264516562cbde473f9a8ffab2918b2fb
    36. 36
      Liu, X.; Shuai, H.-L.; Liu, Y.-J.; Huang, K.-J. An Electrochemical Biosensor for DNA Detection Based on Tungsten Disulfide/Multi-Walled Carbon Nanotube Composites and Hybridization Chain Reaction Amplification. Sensors Actuators B Chem. 2016, 235, 603– 613,  DOI: 10.1016/j.snb.2016.05.132
      36
      An electrochemical biosensor for DNA detection based on tungsten disulfide/multi-walled carbon nanotube composites and hybridization chain reaction amplification
      Liu, Xue; Shuai, Hong-Lei; Liu, Yu-Jie; Huang, Ke-Jing
      Sensors and Actuators, B: Chemical (2016), 235 (), 603-613CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
      We report the prepn. and characterization of tungsten disulfide-multi-walled carbon nanotubes (WS2-MWCNTs) composite via a simple hydrothermal process and demonstrate its application as a biosensing platform for ultrasensitive detn. of hepatitis B virus genomic DNA coupled with hybridization chain reaction (HCR) signal amplification. The sensing platform includes capture DNA probe (cDNA), auxiliary DNA, two DNA hairpins, and detection signal is amplified by horse radish peroxidase (HRP) on the DNA duplex. The biosensor is fabricated with the cDNA labeled at 3' end using thiol immobilized on the WS2-MWCNTs/Au nanoparticels modified electrode. CDNA fixed onto electrode surface then reacts with target DNA through the 3 end of auxiliary DNA. The remaining segment on 5' end of auxiliary DNA then takes turns to open two alternating DNA hairpins. This leads to a HCR events to produce a nicked double-helix. A large amt. of HRP is then combined on DNA helix by affinity interaction of biotin-avidin, each of which amplifies the final electrochem. signal through the catalytic reaction of H2O2 and hydroquinol. Under optimal conditions, a dynamic range of 10 fM-0.1 nM is obtained with a detection limit of 2.5 fM. Synergistic effect of WS2-MWCNTs composite and HCR have proven to greatly improve sensitivity for DNA detection.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps1Wqu7w%253D&md5=5adecb5fa75b30ffedd3db4582a291dd
    37. 37
      Magnusson, B. The Fitness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics. Eurachem Guidel. 2014, na
      There is no corresponding record for this reference.
    38. 38
      Keighley, S. D.; Li, P.; Estrela, P.; Migliorato, P. Optimization of DNA Immobilization on Gold Electrodes for Label-Free Detection by Electrochemical Impedance Spectroscopy. Biosens. Bioelectron. 2008, 23 (8), 1291– 1297,  DOI: 10.1016/j.bios.2007.11.012
      38
      Optimization of DNA immobilization on gold electrodes for label-free detection by electrochemical impedance spectroscopy
      Keighley, Simon D.; Li, Peng; Estrela, Pedro; Migliorato, Piero
      Biosensors & Bioelectronics (2008), 23 (8), 1291-1297CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      The ability to immobilize DNA probes onto gold substrates at an optimum surface d. is key in the development of a wide range of DNA biosensors. We present a method to accurately control probe DNA surface d. by the simultaneous co-immobilization of thiol modified probes and mercaptohexanol. Probe surface d. is controlled by the thiol molar ratio in soln., with a linear relationship between thiol molar ratio and probe d. spanning (1-9) × 1012/cm2. The probe surface d. per microscopic surface area was detd. using chronocoulometry, and a detailed anal. of the method presented. Using this sample prepn. method, the effect of probe d. and hybridization on the charge transfer resistance with the neg. charged ferri/ferrocyanide redox couple was detd. Above a threshold probe surface d. of 2.5 × 1012/cm2, electrostatic repulsion from the neg. charged DNA modulates the charge transfer resistance, allowing hybridization to be detected. Below the threshold d. no change in charge transfer resistance with probe d. or with hybridization occurs. The probe surface d. was optimized to obtain the max. percentage change in charge transfer resistance with hybridization.
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    39. 39
      Kim, H. S.; Farmer, B. L.; Yingling, Y. G. Effect of Graphene Oxidation Rate on Adsorption of Poly-Thymine Single Stranded DNA. Adv. Mater. Interfaces 2017, 4 (8), 1601168,  DOI: 10.1002/admi.201601168
      There is no corresponding record for this reference.
    40. 40
      Zhang, D. Y.; Seelig, G. Dynamic DNA Nanotechnology Using Strand-Displacement Reactions. Nat. Chem. 2011, 3 (2), 103– 113,  DOI: 10.1038/nchem.957
      40
      Dynamic DNA nanotechnology using strand-displacement reactions
      Zhang, David Yu; Seelig, Georg
      Nature Chemistry (2011), 3 (2), 103-113CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      A review. The specificity and predictability of Watson-Crick base pairing make DNA a powerful and versatile material for engineering at the nanoscale. This has enabled the construction of a diverse and rapidly growing set of DNA nanostructures and nanodevices through the programmed hybridization of complementary strands. Although it had initially focused on the self-assembly of static structures, DNA nanotechnol. is now also becoming increasingly attractive for engineering systems with interesting dynamic properties. Various devices, including circuits, catalytic amplifiers, autonomous mol. motors and reconfigurable nanostructures, have recently been rationally designed to use DNA strand-displacement reactions, in which two strands with partial or full complementarity hybridize, displacing in the process one or more pre-hybridized strands. This mechanism allows for the kinetic control of reaction pathways. Here, the authors review DNA strand-displacement-based devices, and look at how this relatively simple mechanism can lead to a surprising diversity of dynamic behavior.
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    41. 41
      Bertucci, A.; Porchetta, A.; Del Grosso, E.; Patiño, T.; Idili, A.; Ricci, F. Protein-Controlled Actuation of Dynamic Nucleic Acid Networks by Using Synthetic DNA Translators. Angew. Chem., Int. Ed. 2020, 59 (46), 20577– 20581,  DOI: 10.1002/anie.202008553
      41
      Protein-Controlled Actuation of Dynamic Nucleic Acid Networks by Using Synthetic DNA Translators
      Bertucci, Alessandro; Porchetta, Alessandro; Del Grosso, Erica; Patino, Tania; Idili, Andrea; Ricci, Francesco
      Angewandte Chemie, International Edition (2020), 59 (46), 20577-20581CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Integrating dynamic DNA nanotechnol. with protein-controlled actuation will expand the authors' ability to process mol. information. The authors have developed a strategy to actuate strand displacement reactions using DNA-binding proteins by engineering synthetic DNA translators that convert specific protein-binding events into trigger inputs through a programmed conformational change. The authors have constructed synthetic DNA networks responsive to two different DNA-binding proteins, TATA-binding protein and Myc-Max, and demonstrated multi-input activation of strand displacement reactions. The authors achieved protein-controlled regulation of a synthetic RNA and of an enzyme through artificial DNA-based communication, showing the potential of the authors' mol. system in performing further programmable tasks.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslGqt7jP&md5=88b58d6f0b1cbcdc4bc74038962f1704
    42. 42
      Hwang, M. T.; Landon, P. B.; Lee, J.; Choi, D.; Mo, A. H.; Glinsky, G.; Lal, R. Highly Specific SNP Detection Using 2D Graphene Electronics and DNA Strand Displacement. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (26), 7088– 7093,  DOI: 10.1073/pnas.1603753113
      42
      Highly specific SNP detection using 2D graphene electronics and DNA strand displacement
      Hwang, Michael T.; Landon, Preston B.; Lee, Joon; Choi, Duyoung; Mo, Alexander H.; Glinsky, Gennadi; Lal, Ratnesh
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (26), 7088-7093CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Single-nucleotide polymorphisms (SNPs) in a gene sequence are markers for a variety of human diseases. Detection of SNPs with high specificity and sensitivity is essential for effective practical implementation of personalized medicine. Current DNA sequencing, including SNP detection, primarily uses enzyme-based methods or fluorophore-labeled assays that are time-consuming, need lab.-scale settings, and are expensive. Previously reported elec. charge-based SNP detectors have insufficient specificity and accuracy, limiting their effectiveness. Here, we demonstrate the use of a DNA strand displacement-based probe on a graphene field effect transistor (FET) for high-specificity, single-nucleotide mismatch detection. The single mismatch was detected by measuring strand displacement-induced resistance (and hence current) change and Dirac point shift in a graphene FET. SNP detection in large double-helix DNA strands (e.g., 47 nt) minimize false-pos. results. Our elec. sensor-based SNP detection technol., without labeling and without apparent cross-hybridization artifacts, would allow fast, sensitive, and portable SNP detection with single-nucleotide resoln. The technol. will have a wide range of applications in digital and implantable biosensors and high-throughput DNA genotyping, with transformative implications for personalized medicine.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps12hsLY%253D&md5=48fa2eb87f7179d33fa628846349a210
    43. 43
      Lv, H.; Li, Q.; Shi, J.; Fan, C.; Wang, F. Biocomputing Based on DNA Strand Displacement Reactions. ChemPhysChem 2021, 22 (12), 1151– 1166,  DOI: 10.1002/cphc.202100140
      43
      Biocomputing Based on DNA Strand Displacement Reactions
      Lv, Hui; Li, Qian; Shi, Jiye; Fan, Chunhai; Wang, Fei
      ChemPhysChem (2021), 22 (12), 1151-1166CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The high sequence specificity and precise base complementary pairing principle of DNA provides a rich orthogonal mol. library for mol. programming, making it one of the most promising materials for developing bio-compatible intelligence. In recent years, DNA has been extensively studied and applied in the field of biol. computing. Among them, the toehold-mediated strand displacement reaction (SDR) with properties including enzyme free, flexible design and precise control, have been extensively used to construct biol. computing circuits. This review provides a systemic overview of SDR design principles and the applications. Strategies for designing DNA-only, enzymes-assisted, other mols.-involved and external stimuli-controlled SDRs are described. The recently realized computing functions and the application of DNA computing in other fields are introduced. Finally, the advantages and challenges of SDR-based computing are discussed.
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    44. 44
      Dunn, K. E.; Trefzer, M. A.; Johnson, S.; Tyrrell, A. M. Investigating the Dynamics of Surface-Immobilized DNA Nanomachines. Sci. Rep. 2016, 6 (1), 29581,  DOI: 10.1038/srep29581
      44
      Investigating the dynamics of surface-immobilized DNA nanomachines
      Dunn, Katherine E.; Trefzer, Martin A.; Johnson, Steven; Tyrrell, Andy M.
      Scientific Reports (2016), 6 (), 29581CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Surface-immobilization of mols. can have a profound influence on their structure, function and dynamics. Toehold-mediated strand displacement is often used in soln. to drive synthetic nanomachines made from DNA, but the effects of surface-immobilization on the mechanism and kinetics of this reaction have not yet been fully elucidated. Here we show that the kinetics of strand displacement in surface-immobilized nanomachines are significantly different to those of the soln. phase reaction, and we attribute this to the effects of intermol. interactions within the DNA layer. We demonstrate that the dynamics of strand displacement can be manipulated by changing strand length, concn. and G/C content. By inserting mismatched bases it is also possible to tune the rates of the constituent displacement processes (toehold-binding and branch migration) independently, and information can be encoded in the time-dependence of the overall reaction. Our findings will facilitate the rational design of surface-immobilized dynamic DNA nanomachines, including computing devices and track-based motors.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFKmtrzO&md5=8d46c910413905994c1df9ad29e7e393
    45. 45
      Broadwater, D. W. B.; Kim, H. D. The Effect of Basepair Mismatch on DNA Strand Displacement. Biophys. J. 2016, 110 (7), 1476– 1484,  DOI: 10.1016/j.bpj.2016.02.027
      45
      The Effect of Basepair Mismatch on DNA Strand Displacement
      Broadwater, D. W. Bo; Kim, Harold D.
      Biophysical Journal (2016), 110 (7), 1476-1484CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
      DNA strand displacement is a key reaction in DNA homologous recombination and DNA mismatch repair and is also heavily utilized in DNA-based computation and locomotion. Despite its ubiquity in science and engineering, sequence-dependent effects of displacement kinetics have not been extensively characterized. Here, we measured toehold-mediated strand displacement kinetics using single-mol. fluorescence in the presence of a single basepair mismatch. The apparent displacement rate varied significantly when the mismatch was introduced in the invading DNA strand. The rate generally decreased as the mismatch in the invader was encountered earlier in displacement. Our data indicate that a single base pair mismatch in the invader stalls branch migration and displacement occurs via direct dissocn. of the destabilized incumbent strand from the substrate strand. We combined both branch migration and direct dissocn. into a model, which we term the concurrent displacement model, and used the first passage time approach to quant. explain the salient features of the obsd. relationship. We also introduce the concept of splitting probabilities to justify that the concurrent model can be simplified into a three-step sequential model in the presence of an invader mismatch. We expect our model to become a powerful tool to design DNA-based reaction schemes with broad functionality.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFKltr8%253D&md5=48eca57f73eaf5de7d14a7eb937506b5
    46. 46
      Li, Q.; Zhao, J.; Liu, L.; Jonchhe, S.; Rizzuto, F. J.; Mandal, S.; He, H.; Wei, S.; Sleiman, H. F.; Mao, H.; Mao, C. A Poly(Thymine)–Melamine Duplex for the Assembly of DNA Nanomaterials. Nat. Mater. 2020, 19 (9), 1012– 1018,  DOI: 10.1038/s41563-020-0728-2
      46
      A poly(thymine)-melamine duplex for the assembly of DNA nanomaterials
      Li, Qian; Zhao, Jiemin; Liu, Longfei; Jonchhe, Sagun; Rizzuto, Felix J.; Mandal, Shankar; He, Huawei; Wei, Sansen; Sleiman, Hanadi F.; Mao, Hanbin; Mao, Chengde
      Nature Materials (2020), 19 (9), 1012-1018CODEN: NMAACR; ISSN:1476-1122. (Nature Research)
      Abstr.: The diversity of DNA duplex structures is limited by a binary pair of hydrogen-bonded motifs. Here we show that poly(thymine) self-assocs. into antiparallel, right-handed duplexes in the presence of melamine, a small mol. that presents a triplicate set of the hydrogen-bonding face of adenine. X-ray crystallog. shows that in the complex two poly(thymine) strands wrap around a helical column of melamine, which hydrogen bonds to thymine residues on two of its three faces. The mech. strength of the thymine-melamine-thymine triplet surpasses that of adenine-thymine base pairs, which enables a sensitive detection of melamine at 3 pM. The poly(thymine)-melamine duplex is orthogonal to native DNA base pairing and can undergo strand displacement without the need for overhangs. Its incorporation into two-dimensional grids and hybrid DNA-small-mol. polymers highlights the poly(thymine)-melamine duplex as an addnl. tool for DNA nanotechnol.
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    47. 47
      Chao, J.; Zhu, D.; Zhang, Y.; Wang, L.; Fan, C. DNA Nanotechnology-Enabled Biosensors. Biosens. Bioelectron. 2016, 76, 68– 79,  DOI: 10.1016/j.bios.2015.07.007
      47
      DNA nanotechnology-enabled biosensors
      Chao, Jie; Zhu, Dan; Zhang, Yinan; Wang, Lianhui; Fan, Chunhai
      Biosensors & Bioelectronics (2016), 76 (), 68-79CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      Biosensors employ biol. mols. to recognize the target and utilize output elements which can translate the biorecognition event into elec., optical or mass-sensitive signals to det. the quantities of the target. DNA-based biosensors, as a sub-field to biosensor, utilize DNA strands with short oligonucleotides as probes for target recognition. Although DNA-based biosensors have offered a promising alternative for fast, simple and cheap detection of target mols., there still exist key challenges including poor stability and reproducibility that hinder their competition with the current gold std. for DNA assays. By exploiting the self-recognition properties of DNA mols., researchers have dedicated to make versatile DNA nanostructures in a highly rigid, controllable and functionalized manner, which offers unprecedented opportunities for developing DNA-based biosensors. In this review, we will briefly introduce the recent advances on design and fabrication of static and dynamic DNA nanostructures, and summarize their applications for fabrication and functionalization of DNA-based biosensors.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1CkurnM&md5=43ccabd2a24b0a8c1d3ca999005cf6c4
    48. 48
      Idili, A.; Parolo, C.; Alvarez-Diduk, R.; Merkoçi, A. Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor. ACS Sensors 2021, 6 (8), 3093– 3101,  DOI: 10.1021/acssensors.1c01222
      48
      Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor
      Idili, Andrea; Parolo, Claudio; Alvarez-Diduk, Ruslan; Merkoci, Arben
      ACS Sensors (2021), 6 (8), 3093-3101CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      The availability of sensors able to rapidly detect SARS-CoV-2 directly in biol. fluids in a single step would allow performing massive diagnostic testing to track in real time and contain the spread of COVID-19. Motivated by this, here, we developed an electrochem. aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quant. measurement of the SARS-CoV-2 spike (S) protein. First, we demonstrated the ability of the selected aptamer to undergo a binding-induced conformational change in the presence of its target using fluorescence spectroscopy. Then, we engineered the aptamer to work as a bioreceptor in the EAB platform and we demonstrated its sensitivity and specificity. Finally, to demonstrate the clin. potential of the sensor, we tested it directly in biol. fluids (serum and artificial saliva), achieving the rapid (minutes) and single-step detection of the S protein in its clin. range.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslegsLvI&md5=eed8021b69f60f966c493363ef2aa479
    49. 49
      Watson, E. E.; Angerani, S.; Sabale, P. M.; Winssinger, N. Biosupramolecular Systems: Integrating Cues into Responses. J. Am. Chem. Soc. 2021, 143 (12), 4467– 4482,  DOI: 10.1021/jacs.0c12970
      49
      Biosupramolecular Systems: Integrating Cues into Responses
      Watson, Emma E.; Angerani, Simona; Sabale, Pramod M.; Winssinger, Nicolas
      Journal of the American Chemical Society (2021), 143 (12), 4467-4482CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A review. Life is orchestrated by biomols. interacting in complex networks of biol. circuitry with emerging function. Progress in different areas of chem. has made the design of systems that can recapitulate elements of such circuitry possible. Herein we review prominent examples of networks, the methodologies available to translate an input into various outputs, and speculate on potential applications and directions for the field. The programmability of nucleic acid hybridization has inspired applications beyond its function in heredity. At the circuitry level, DNA provides a powerful platform to design dynamic systems that respond to nucleic acid input sequences with output sequences through diverse logic gates, enabling the design of ever more complex circuitry. In order to interface with more diverse biomol. inputs and yield outputs other than oligonucleotide sequences, an array of nucleic acid conjugates have been reported that can engage proteins as their input and yield a turn-on of enzymic activity, a bioactive small mol., or morphol. changes in nanoobjects. While the programmability of DNA makes it an obvious starting point to design circuits, other biosupramol. interactions have also been demonstrated, and harnessing progress in protein design is bound to deliver further integration of macromols. in artificial circuits.
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    50. 50
      Rossetti, M.; Bertucci, A.; Patiño, T.; Baranda, L.; Porchetta, A. Programming DNA-Based Systems through Effective Molarity Enforced by Biomolecular Confinement. Chem.─Eur. J. 2020, 26 (44), 9826– 9834,  DOI: 10.1002/chem.202001660
      50
      Programming DNA-Based Systems through Effective Molarity Enforced by Biomolecular Confinement
      Rossetti, Marianna; Bertucci, Alessandro; Patino, Tania; Baranda, Lorena; Porchetta, Alessandro
      Chemistry - A European Journal (2020), 26 (44), 9826-9834CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The fundamental concept of effective molarity is obsd. in a variety of biol. processes, such as protein compartmentalization within organelles, membrane localization and signaling paths. To control mol. encountering and promote effective interactions, nature places biomols. in specific sites inside the cell in order to generate a high, localized concn. different from the bulk concn. Inspired by this mechanism, scientists have artificially recreated in the lab the same strategy to actuate and control artificial DNA-based functional systems. Here, it is discussed how harnessing effective molarity has led to the development of a no. of proximity-induced strategies, with applications ranging from DNA-templated org. chem. and catalysis, to biosensing and protein-supported DNA assembly.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1ymtr7F&md5=96d7fd8863685c223878abffdd0a2ba5
    51. 51
      Ranallo, S.; Prévost-Tremblay, C.; Idili, A.; Vallée-Bélisle, A.; Ricci, F. Antibody-Powered Nucleic Acid Release Using a DNA-Based Nanomachine. Nat. Commun. 2017, 8 (1), 15150,  DOI: 10.1038/ncomms15150
      51
      Antibody-powered nucleic acid release using a DNA-based nanomachine
      Ranallo, Simona; Prevost-Tremblay, Carl; Idili, Andrea; Vallee-Belisle, Alexis; Ricci, Francesco
      Nature Communications (2017), 8 (), 15150CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      A wide range of mol. devices with nanoscale dimensions have been recently designed to perform a variety of functions in response to specific mol. inputs. Only limited examples, however, utilize antibodies as regulatory inputs. In response to this, here we report the rational design of a modular DNA-based nanomachine that can reversibly load and release a mol. cargo on binding to a specific antibody. We show here that, by using three different antigens (including one relevant to HIV), it is possible to design different DNA nanomachines regulated by their targeting antibody in a rapid, versatile and highly specific manner. The antibody-powered DNA nanomachines we have developed here may thus be useful in applications like controlled drug-release, point-of-care diagnostics and in vivo imaging.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsVaju74%253D&md5=05e1a0a41db29f7dbf84e0193a0f179e
    52. 52
      Engelen, W.; Meijer, L. H. H.; Somers, B.; de Greef, T. F. A.; Merkx, M. Antibody-Controlled Actuation of DNA-Based Molecular Circuits. Nat. Commun. 2017, 8 (1), 14473,  DOI: 10.1038/ncomms14473
      52
      Antibody-controlled actuation of DNA-based molecular circuits
      Engelen, Wouter; Meijer, Lenny H. H.; Somers, Bram; de Greef, Tom F. A.; Merkx, Maarten
      Nature Communications (2017), 8 (), 14473CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      DNA-based mol. circuits allow autonomous signal processing, but their actuation has relied mostly on RNA/DNA-based inputs, limiting their application in synthetic biol., biomedicine and mol. diagnostics. Here we introduce a generic method to translate the presence of an antibody into a unique DNA strand, enabling the use of antibodies as specific inputs for DNA-based mol. computing. Our approach, antibody-templated strand exchange (ATSE), uses the characteristic bivalent architecture of antibodies to promote DNA-strand exchange reactions both thermodynamically and kinetically. Detailed characterization of the ATSE reaction allowed the establishment of a comprehensive model that describes the kinetics and thermodn. of ATSE as a function of toehold length, antibody-epitope affinity and concn. ATSE enables the introduction of complex signal processing in antibody-based diagnostics, as demonstrated here by constructing mol. circuits for multiplex antibody detection, integration of multiple antibody inputs using logic gates and actuation of enzymes and DNAzymes for signal amplification.
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    53. 53
      Li, F.; Zhang, H.; Wang, Z.; Li, X.; Li, X.-F.; Le, X. C. Dynamic DNA Assemblies Mediated by Binding-Induced DNA Strand Displacement. J. Am. Chem. Soc. 2013, 135 (7), 2443– 2446,  DOI: 10.1021/ja311990w
      53
      Dynamic DNA Assemblies Mediated by Binding-Induced DNA Strand Displacement
      Li, Feng; Zhang, Hongquan; Wang, Zhixin; Li, Xukun; Li, Xing-Fang; Le, X. Chris
      Journal of the American Chemical Society (2013), 135 (7), 2443-2446CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Dynamic DNA assemblies, including catalytic DNA circuits, DNA nanomachines, mol. translators, and reconfigurable nanostructures, have shown promising potential to regulate cell functions, deliver therapeutic reagents, and amplify detection signals for mol. diagnostics and imaging. However, such applications of dynamic DNA assembly systems have been limited to nucleic acids and a few small mols., due to the limited approaches to trigger the DNA assemblies. Herein, we describe a binding-induced DNA strand displacement strategy that can convert protein binding to the release of a predesigned output DNA at room temp. with high conversion efficiency and low background. This strategy allows us to construct dynamic DNA assembly systems that are able to respond to specific protein binding, opening an opportunity to initiate dynamic DNA assembly by proteins.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslSqt7c%253D&md5=62fc94dfc7d9db45621b7a6a19eb8dde
    54. 54
      Avakyan, N.; Greschner, A. A.; Aldaye, F.; Serpell, C. J.; Toader, V.; Petitjean, A.; Sleiman, H. F. Reprogramming the Assembly of Unmodified DNA with a Small Molecule. Nat. Chem. 2016, 8 (4), 368– 376,  DOI: 10.1038/nchem.2451
      54
      Reprogramming the assembly of unmodified DNA with a small molecule
      Avakyan, Nicole; Greschner, Andrea A.; Aldaye, Faisal; Serpell, Christopher J.; Toader, Violeta; Petitjean, Anne; Sleiman, Hanadi F.
      Nature Chemistry (2016), 8 (4), 368-376CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The ability of DNA to store and encode information arises from base pairing of the four-letter nucleobase code to form a double helix. Expanding this DNA 'alphabet' by synthetic incorporation of new bases can introduce new functionalities and enable the formation of novel nucleic acid structures. However, reprogramming the self-assembly of existing nucleobases presents an alternative route to expand the structural space and functionality of nucleic acids. Here we report the discovery that a small mol., cyanuric acid, with three thymine-like faces, reprogrammes the assembly of unmodified poly(adenine) (poly(A)) into stable, long and abundant fibers with a unique internal structure. Poly(A) DNA, RNA and peptide nucleic acid (PNA) all form these assemblies. Our studies are consistent with the assocn. of adenine and cyanuric acid units into a hexameric rosette, which brings together poly(A) triplexes with a subsequent cooperative polymn. Fundamentally, this study shows that small hydrogen-bonding mols. can be used to induce the assembly of nucleic acids in water, which leads to new structures from inexpensive and readily available materials.
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    55. 55
      Jash, B.; Müller, J. Metal-Mediated Base Pairs: From Characterization to Application. Chem.─Eur. J. 2017, 23 (68), 17166– 17178,  DOI: 10.1002/chem.201703518
      55
      Metal-Mediated Base Pairs: From Characterization to Application
      Jash, Biswarup; Mueller, Jens
      Chemistry - A European Journal (2017), 23 (68), 17166-17178CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The study of metal-mediated base pairs and the development of their applications represent a prominent area of research at the border of bioinorg. chem. and supramol. coordination chem. In metal-mediated base pairs, the complementary nucleobases in a nucleic acid duplex are connected by coordinate bonds to an embedded metal ion rather than by hydrogen bonds. Because metal-mediated base pairs facilitate a site-specific introduction of metal-based functionality into nucleic acids, they are ideally suited for use in DNA nanotechnol. This minireview gives an overview of the general requirements that need to be considered when devising a new metal-mediated base pair, both from a conceptual and from an exptl. point of view. In addn., it presents selected recent applications of metal-modified nucleic acids to indicate the scope of metal-mediated base pairing.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.1c05294.

    • DNA sequences, enzyme-based electrochemical signal, calculation of probe density, efficacy of electrode backfilling using pyrene, strand displacement using mismatched sequences, and melamine electroactivity in the potential range of interest (PDF)


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