DNA-Mimicking Metal–Organic Frameworks with Accessible Adenine Faces for Complementary Base Pairing

Biologically derived metal–organic frameworks (Bio-MOFs) are significant, as they can be used in cutting-edge biomedical applications such as targeted gene delivery. Herein, adenine (Ade) and unnatural amino acids coordinate with Zn2+ to produce biocompatible frameworks, KBM-1 and KBM-2, with extremely defined porous channels. They feature an accessible Watson–Crick Ade face that is available for further hydrogen bonding and can load single-stranded DNA (ssDNA) with 13 and 41% efficiency for KBM-1 and KBM-2, respectively. Treatment of these frameworks with thymine (Thy), as a competitive guest for base pairing with the Ade open sites, led to more than 50% reduction of ssDNA loading. Moreover, KBM-2 loaded Thy-rich ssDNA more efficiently than Thy-free ssDNA. These findings support the role of the Thy-Ade base pairing in promoting ssDNA loading. Furthermore, theoretical calculations using the self-consistent charge density functional tight-binding (SCC-DFTB) method verified the role of hydrogen bonding and van der Waals type interactions in this host–guest interface. KBM-1 and KBM-2 can protect ssDNA from enzymatic degradation and release it at acidic pH. Most importantly, these biocompatible frameworks can efficiently deliver genetic cargo with retained activity to the cell nucleus. We envisage that this class of Bio-MOFs can find immediate applicability as biomimics for sensing, stabilizing, and delivering genetic materials.


Experimental Section
Materials. All reagents and solvents were purchased from commercial sources and used without further purification. Linker L has been synthesized from previously reported procedure. 1 Physical Measurements. The Fourier transform infrared (FTIR) spectra were recorded using a Thermo Scientific spectrometer (Nicolet iS10). PXRD patterns were recorded using Cu-Kα radiation (1.5418 Å) on a Bruker D8 Advance diffractometer.
Thermogravimetric analysis (TGA) measurements were carried out on a Q5000 (TA Instruments) and the samples were heated from room temperature to 600 °C at a rate of 5 °C min -1 under N2 atmosphere. Low-pressure gas adsorption measurements were performed using a Microactive 4.0 ASAP 2020 instrument. To remove all guest solvents in the framework, the fresh samples were first solvent-exchanged with dry acetone at least 10 times within 2 days and degassed at 343 K for 12 h. The sorption measurement was maintained at 77 K under liquid nitrogen. Room temperature CO2 Gas sorption experiments were tested on a Micromeritics ASAP 2020 instrument. Solid state NMR spectra were acquired on an Avance III 600 WB spectrometer equipped with a 3.2 mm low-temperature CPMAS probe capable of spinning speed up to 24 kHz. Transmission electron microscopy (TEM) was conducted on FEI Titan-ST electron microscope.
Dynamic light scattering (DLS) and zeta potential analysis were performed using a Malvern Nano ZS instrument at 25 °C.
Single Crystal X-ray Diffraction. The crystal and refinement data for KBM-1 and 2 were collected in Table S1 and Table S2. In this case, a crystal of suitable size was selected from the mother liquor and immersed in paratone oil and then it was mounted on the tip of glass fiber and cemented using epoxy resin. Single crystal X-ray data were collected at 120 K on a Bruker SMART APEX II CCD diffractometer using graphite-monochromated Mo-Kα radiation (0.71073 Å). The linear absorption coefficients, scattering factors for the atoms and the anomalous dispersion corrections were taken from International Tables for X-ray Crystallography. The data integration and reduction were processed with SAINT S3 software. 2 An empirical absorption correction was applied to the collected reflections with SADABS using XPREP. 3 The structure was solved by the direct method using SHELXTL and was refined on F 2 by a full-matrix least-squares technique using the SHELXL-2014 program package. 4-6 For all the cases, non-hydrogen atoms were refined anisotropically.
Attempts to identify the highly disordered solvent molecules were failed. Instead, a new set of F 2 (hkl) values with the contribution from the solvent molecules withdrawn were obtained by the SQUEEZE 7 procedure implemented in PLATON. 8 The cationic guests Me2NH2 + could be located in the channels from Difference Fourier Map for KBM-1.  12 and Grimme's D3 type dispersion was included. 13 Since the MOF is an infinite system, periodic boundary condition was applied for the both frameworks, and the cell parameters were fixed to the experimental values during the optimizations. After two Thy are introduced into the pore channels of KBM-1 and KBM-2, we again optimized Thy@KBM-1 and Thy@KBM-2 with the fixed cell parameter as well.
To shed light on the noncovalent interactions (NCI) between the Thy and KBM frameworks of Thy@KBM-1 and Thy@KBM-2, NCIPLOT software was used. [14][15] The relation between the electron density () and its reduced density gradient (s) is as follows, where  is the gradient of . The promolecular approach has been considered for the computations in this work. The sign(2) as the reduced density gradient (s) is plotted using VMD visualization package. 16
Cells in media containing MOFs were incubated for 24 hours. Then, the MTT assay was