ACS Editors’ Choice

Ammonia (NH₃) is increasingly recognized as a promising hydrogen (H₂) carrier due to its high H₂ content, ease of liquefaction, and existing distribution infrastructure. This review focuses on the decomposition of NH₃ for H₂ production, a process that holds significant potential for increasing energy resiliency. It examines the latest developments in NH₃ decomposition technologies, including catalytic and non-catalytic methods. Special attention is given to the advancements in catalyst design, particularly those involving cost-effective and abundant materials that improve reaction kinetics and efficiency. The review also explores innovative approaches, such as plasma-assisted, electrocatalytic, and photocatalytic decomposition, which offer alternative routes for H₂ generation. By assessment of the performance, scalability, and economical feasibility of these technologies, the review aims to highlight the challenges and opportunities in utilizing NH₃ as an energy vector. Furthermore, it outlines future research directions necessary to overcome current limitations and to facilitate the integration of NH₃ decomposition into the broader H₂ economy, ultimately contributing to a resilient energy future.

Perylenediimides (PDIs) are among the best-known chromophores for optoelectronic applications. Their photophysics in oxygen-rich environments remains, however, underexplored. In this study, we investigate three different PDI derivatives using steady-state and time-resolved absorption and emission spectroscopy in toluene with different oxygen concentrations. Unsubstituted PDI and 1,7-bay-substituted PDI featuring diphenylphenoxy groups exhibit oxygen-mediated sequential down-conversion. Upon photoexcitation, the singlet excited state (S₁) of PDIs interacts with molecular oxygen (³O₂) to generate singlet oxygen (¹O₂) via the formation of the triplet excited state (T₁) of PDIs. Subsequently, (T₁)s of PDIs sensitize an additional ³O₂ to produce a second ¹O₂. Overall, one (S₁) produces two ¹O₂. Importantly, this process depends on energy requirements: on one hand, the energy difference between (S₁) and (T₁), and on the other hand, the (T₁) energy level should exceed that of ¹O₂. Our work illustrates the oxygen-mediated sequential down-conversion in perylenediimides and reveals its effects.

Enantioselective oxygenation of unactivated C(sp³)–H bonds via asymmetric metalation remains an unsolved challenge. Herein we report the development of a Pd-catalyzed, enantioselective C(sp³)–H tosylation of native amides with NaOTs as the nucleophile, representing a rare example of enantioselective C–H functionalization with a nucleophilic coupling partner. High enantioselectivity in this reaction is achieved by chiral monoprotected amino sulfonamide (MPASA) ligands. Substantial enhancement of the enantioselectivity by silver salt additives was also observed. Through desymmetrization of the readily available isopropyl moiety, structurally diverse β-tosylated amides bearing an α-methyl stereocenter were obtained with high yield and enantioselectivity, which complements the current enzymatic method for making Roche ester chiral synthon. The tosylated products are highly versatile chiral building blocks for further diversifications with nitrogen, oxygen, and other nucleophiles, thus providing a platform for constructing chiral methyl stereocenters.

ZnZrO_x is a promising oxide component for direct syngas conversion via oxide–zeolite bifunctional catalysis, while rational design of active centers within the composite oxide remains limited. In this study, through ab initio thermodynamics, molecular dynamics, and microkinetic modeling, we find that diverse subnanometer ZnO_x species, including single-site, single-chain, and single-layer configurations, can form on active ZrO₂ surfaces under the reaction conditions. These confined ZnO_x species weaken CO adsorption but enhance heterolytic H₂ dissociative adsorption, favoring continuous hydrogenation of CO to methanol over direct or H-assisted CO dissociation. For single-layer ZnO_x structures, a double-chain film grows on a monoclinic ZrO₂ (m-ZrO₂) surface while a graphene-like film emerges on tetragonal ZrO₂ (t-ZrO₂). These single-layer ZnO_x species exhibit higher methanol formation activity than their single-chain or single-site counterparts, which benefit from sufficient sites for adsorption of intermediates and a suitable space for bonding of H with C in CHO. Furthermore, the double-chain ZnO_x film confined on m-ZrO₂ exposes octahedral Zn_oct sites, which are more reactive than the triangular Zn_tri sites in the graphene-like ZnO_x on t-ZrO₂, despite both sites being nominally three-coordinate. These findings provide insights for the precise design of composite oxide/oxide catalysts through fine-tuning overlayer coverage and/or support surface properties.

Cancer remains the leading cause of death, with chemotherapy, radiotherapy, and surgical resection being the primary treatment methods. However, chemotherapy’s side effects, surgical limitations, and drug resistance present significant challenges. Small interfering RNA (siRNA) has emerged as a promising tool in cancer therapy due to its ability to silence disease-related genes selectively. Recent advancements in nonviral delivery systems, particularly cell-penetrating peptides (CPPs), have enhanced the efficacy of siRNA delivery. The use of siRNA as a therapeutic tool in cancer treatment has been reported in the literature. However, silencing only one target protein has only a minor effect on tumor cell proliferation, as previously shown for WRAP-based nanoparticles targeting cyclin-dependent kinase 4 (CDK4) in human U87 glioblastoma cells. Here, we designed a more sophisticated approach to enhance therapeutic efficacy, encapsulating multiple siRNAs targeting CDK4, cyclin D1 (CD1), and MCL-1 proteins. The siRNA cocktail, delivered via WRAP5 nanoparticles, effectively silenced these targets and reduced cell proliferation in human U87 glioblastoma cells. Furthermore, the nanoparticles also demonstrated potential therapeutic impact in gastrointestinal stromal tumors (GIST), a rare cancer characterized by its tendency to resist standard treatments. This study highlights the versatility of WRAP5 nanoparticles as a platform for personalized cancer therapy, suggesting that siRNA delivery systems may be tailored to specific cancer types for more effective treatment strategies.

The biointerface between biological tissues and electronic devices serves as a medium for matter transport, signal transmission, and energy conversion. However, significant disparities in properties, such as mechanical modulus and water content, between tissues and electronics, present a key challenge in bioelectronics, leading to biointerface mismatches that severely impact their performance and long-term stability. Organic electrochemical transistors (OECTs), fabricated with soft, hydrophilic organic semiconductors, offer unique advantages, including low operating voltage, high transconductance, and compatibility with aqueous environments. These attributes position OECTs as promising candidates for ideal biointerfaces. As neural probes, OECTs have demonstrated superior biocompatibility and signal detection capabilities compared to conventional metal electrodes and inorganic semiconductors. Despite these advantages, the applications of OECT as biointerfaces remain constrained by several limitations, including limited performance, poor stability, mismatches among p-type, n-type, and ambipolar semiconductors, relatively high Young’s modulus, and unsatisfactory biointerfacial properties.

In this Account, we summarize our group’s efforts to improve both the electronic and biointerfacial properties of OECTs, encompassing structure–property relationship studies, device optimization/fabrication, and biointerface enhancement. To elucidate the structure–property relationship, we explored the material design strategies and device optimization approaches for high-performance OECTs, highlighting the critical role of doped state properties in the OECT system. Recognizing the unique characteristics of OECTs, we designed hydrophilic polymer backbones to replace conventional neutral ones. These hydrophilic ionic backbones foster strong intermolecular interactions, resulting in improved operational stability. Additionally, we demonstrate that constructing high-spin polymers enables the development of high-performance, balanced ambipolar materials. Based on these materials innovations, we advanced fabrication methods of OECT-based logic circuits and fiber-based OECTs, realizing complementary and ambipolar logic circuits, as well as wearable fabric-based biosensors. Finally, we integrated the exceptional biointerface properties of hydrogels with organic semiconductors, pioneering semiconducting hydrogels that exhibit outstanding mechanical, electrical, and biointerfacial properties. These materials enable efficient in vivo amplification of electrophysiological signals. The concept and realization of semiconducting hydrogels redefine the scope of OECTs and hydrogel electronics, providing a novel approach to ideal biointerfaces. We hope that the perspectives shared in this Account will inspire the development of next generation bioelectronic devices with enhanced biointerface compatibility and expanded functionalities.

Living emulsions, which incorporate active bacteria into oil–water multiphase systems, represent an innovative integration of microbiology and colloid science. The active role of living species offers dynamic and adaptive functionalities absent in traditional emulsions. In particular, bacteria, as active colloids, have the potential to fulfill roles such as Pickering stabilizers, biomanufacturers, and biomediators to functionalize, reinforce, or degrade with multiphasic components. Selecting bacteria with appropriate surface properties (e.g., wettability, surface charge) enables their adsorption at oil–water interfaces, forming living Pickering emulsions for food or biocatalyst applications. Beyond static stabilization, bacteria-driven biosynthesis of materials like bacterial nanocellulose (BNC) at interfaces could promote advanced biofabrication of structured microcapsules and emulgels; whereas, conversely, hydrocarbon-degrading bacteria have been recognized to disrupt emulsions by metabolizing oil phases, offering bioremediation solutions for oil spills. These active emulsion systems highlight bacterial adaptability to extreme conditions and biodegradability, aligning with ecological sustainability. By merging microbial activity with emulsion science, living emulsions unlock smart, multifunctional systems for industries ranging from food to environmental technology.

In polyamides, hydrogen bonding and conformations of amide motifs are strongly influenced by pH, ions and their concentration, and water molecules and their structure. To fulfill the physical requirements for ultradrawing of polyamide 6, we first complete our fundamental insight into the role of water, ions, and polyamide 6 crystal structures on the concept of reversible shielding of hydrogen bonds. The reversible shielding depends on a complementary superchaotropic effect of anions and the kosmotropic effect of cations, locally affecting the structuring and interactions of water. We show that in the presence of large halogen anions, specifically polyiodides, crystallization from the random coil state or during crystallographic reorganization is suppressed by hydrophobic hydration. Among the cations, hydrated lithium and calcium cations promote the formation of polyiodides, specifically I₃^–. The small size of lithium cations entails high diffusivity with water molecules, retrospectively effectively shielding the hydrogen bonding in the crystals. Upon reorganization of the conformationally distorted β phase upon heating and close to the boiling point of water, ions promote gel formation. The gel can be extruded and shaped, e.g., into monofilaments at 85 °C, and at room temperature, it can be stretched to a draw ratio of 25 to secure chain orientation. After immersion in water to remove the ions and restore the amide–amide hydrogen bonds, postdrawing and drying render high anisotropy, oriented chain crystals of high perfection, and tensile modulus and strength up to ∼19 × 10³ and ∼1140 MPa, respectively. The process holds potential in achieving extended chain crystals desired for ultimate mechanical properties.

Perovskite solar cells (PSCs) have experienced a rapid increase in power conversion efficiency (PCE) over the past decade, positioning them as strong candidates for next-generation commercial photovoltaics (PVs). Their tunable bandgap makes them ideal for tandem configurations, especially when coupled with crystalline silicon (Si) bottom cells; this combination offers the potential to exceed the PCE limits of single-junction devices and is arguably essential for successful market entry of perovskite technologies. However, commercialization of perovskite/Si tandems also demands enhanced durability and reliable integration into PV modules, withstanding long-term outdoor exposure. Besides light, temperature, and voltage bias stress, difficulties to overcome involve the mechanical stability and performance of the interfaces within tandem devices, which may degrade over time under real-world operating conditions. This review explores the critical role of interface engineering in addressing these challenges, reviewing the latest advancements in interface materials, encapsulation strategies, and novel integration techniques. By identification of the critical issues and adequate solutions, this paper provides a vision for the future of perovskite/Si tandem solar cells, emphasizing the importance of advanced manufacturing techniques and interdisciplinary research but also policy support.

Luminescent nano/micro molecular crystals with well-defined shapes and morphologies have exhibited great potential for various photonic applications. The molecular orientation and packing greatly influence the optical and electronic characters of the crystals. Noncovalent intermolecular interactions can not only determine the growth direction but also induce the formation of polymorphs, bringing more possibilities for the property optimization and functional applications. Besides, light-harvesting energy transfer (LHEnT) is a vital process in natural photosynthesis, the mimic of which provides a simple and practical means for solar energy conversion and the preparation of luminescent materials. With an energy donor and acceptor pair with suitable energy levels and similar molecular size and solubility, it is convenient to fabricate LHEnT molecular crystals with tunable optoelectronic and emission properties by dispersing acceptors into the donor lattices.

We describe in this Account our recent research progress on the use of octahedral iridium (Ir^III) and ruthenium (Ru^II) complexes to prepare luminescent crystals for potential applications in nanophotonics. By introducing simple substituents on the coordination ligands, such as a methyl group, fluoro atom, and trifluoromethyl group, as the functional unit to direct assembly, we have been able to obtain well-defined nano/microcrystals from these complexes. Furthermore, by using a molecular doping strategy accompanied by the LHEnT process, the obtained binary crystals show efficient and tunable luminescence properties. With these endeavors, we have realized the luminescence amplification of an Ir^III energy acceptor that suffers severely from the aggregation-caused quenching effect. Molecular crystals with high-performance linearly polarized luminescence, circularly polarized luminescence, and electrochemiluminescence have been prepared, and their applications in polarized light waveguides and chemical sensing have been demonstrated. By using a stepwise binary assembly method, optical heterostructures are prepared to show their potential in optical information processing and thermosensing.

6PPD-quinone, a degradation product of the rubber antiozonant 6PPD that is frequently added to tires, has previously been identified as a causative agent of urban runoff mortality syndrome in salmonids. Previous high-throughput phenotypic profiling (HTPP) studies using the Cell Painting assay in the RTgill-W1 rainbow trout cell line have demonstrated that 6PPD-quinone toxicity occurs at much lower concentrations than the 6PPD parent molecule, which is consistent with available in vivo toxicity data in rainbow trout. Current research efforts include identifying alternative antiozonant compounds to potentially replace 6PPD in tire manufacturing. To fill bioactivity data gaps for potential 6PPD alternatives, 18 compounds including other substituted p-phenylenediamines (PPD) and PPD-quinones were assayed using HTPP in RTgill-W1 cells. 7PPD-quinone and 77PD-quinone produced changes in cellular phenotype similar to those of 6PPD-quinone at comparable concentrations. IPPD-quinone produced changes in cellular phenotype at higher concentrations than 6PPD-quinone, with a phenotypic profile that was most similar to its parent molecule IPPD. These findings suggest that 7PPD-quinone and 77PD-quinone may exhibit similar effects in rainbow trout and potentially other 6PPD-quinone sensitive salmonids. In contrast, IPPD may be less toxic to salmonids than 6PPD, given the relative lack of bioactivity of IPPD-quinone compared to 6PPD-quinone.

Docking-based virtual screening tools customized to mine ultralarge chemical spaces are consistently reported to yield both higher hit rates and more potent ligands than that achieved by conventional docking of smaller million-sized compound libraries. This remarkable achievement is however counterbalanced by the absolute necessity to design an efficient postprocessing of the millions of potential virtual hits for selecting a few chemically diverse compounds for synthesis and biological evaluation. We here retrospectively analyzed ten successful ultralarge virtual screening hit lists that underwent in vitro binding assays, for binding affinity prediction using eight rescoring methods including simple empirical scoring functions, machine learning, molecular-mechanics and quantum-mechanics approaches. Although the best predictions usually rely on the most sophisticated methods, none of the tested rescoring methods could robustly distinguish known binders from inactive compounds, across all assays. Energy refinement of protein–ligand complexes, prior to rescoring, marginally helped molecular mechanics and quantum mechanics approaches but deteriorates predictions from empirical and machine learning scoring functions.

Gold-based nanomaterials have marked the last few decades with the emergence of new medical technologies presenting unique features. For instance, the conjugation of gold nanoparticles (AuNPs) and nucleic acids has allowed the creation of nanocarriers with immense promise for gene therapy applications. Although the use of lipid particles as RNA delivery vectors has been broadly explored, this review aims to focus on the limited models reported for the conjugation of RNA with AuNPs. This is nonetheless unexpected regarding the manifold strategies existing to conjugate DNA to gold nanoparticles, which are exhaustively listed in this paper. Furthermore, new processes such as fast microwave and freezing methods have been described very recently, and it therefore seemed necessary to review these recent but promising conjugation pathways and to pick out those applicable to RNA. Indeed, RNA is considerably more attractive than DNA for therapeutic purposes, but its low stability involves numerous difficulties in the construction of effective nanodevices. However, from the many approaches developed for DNA, it turns out that just two of them are frequently used for the building of RNA delivery platforms based on gold: the salt-aging method with thiolated RNA strands and physisorption. However, both approaches present strong limitations such as the low stability of the Au–S bond and the potential cytotoxicity of polycations. To conclude, this general assessment highlights that the exploration of innovating approaches implying different chemistries is needed for the creation of more robust and shapeable AuNPs-RNA conjugates.

Cryptosporidiosis poses a significant health threat to young children and immunocompromised individuals due to the lack of effective therapies. Here, we demonstrate that the Cryptosporidium parvum redox system is fundamentally different from their human host. Humans possess independent glutathione (GSH) and thioredoxin (Trx) pathways. Cryptosporidium lacks authentic glutathione reductase (GR), and we hypothesize that it most likely utilizes the Trx reductase (TrxR) plus Trx couple to maintain GSH in its reduced state. Given the central role of CpTrxR in the parasite’s redox homeostasis, we focus on its functional and structural characterization. We find that the combination of CpTrxR andC. parvum Trx efficiently reduces oxidized GSH, in effect functioning as a GR. Auranofin, a gold-containing compound, is known to kill parasites in culture, and here we demonstrate that CpTrxR is irreversibly inhibited by this compound. The crystallographic structures of CpTrxR, a type II TrxR characterized by the distinctive C-terminal -CGGGKCG motif found exclusively in apicomplexan parasites, including Plasmodium spp., the causative agents of malaria, are presented. Our study characterizes three unprecedented catalytically competent intermediates of the C-terminal tail in the so-called “in” conformations, providing insights into the structural and functional properties of type II TrxR. These findings offer valuable information for the design of CpTrxR inhibitors, addressing the pressing need for new therapeutic options against cryptosporidiosis, particularly in populations where current treatments are insufficiently effective.

Organic battery electrode materials are key enablers of different postlithium cell chemistries. As a p-type compound with up to two reversible redox processes at relatively high potentials of 3.5 and 4.1 V vs. Li/Li⁺, phenothiazine is an excellently suited redox-active group. It can easily be functionalized and incorporated into polymeric structures, a prerequisite to obtain insolubility in liquid battery electrolytes. Phenothiazine tends to exhibit π-interactions (π*−π*-interactions) to stabilize its radical cationic form, which can increase the stability of the oxidized form but can also strongly influence its cycling performance as a battery electrode material. In recent years, we investigated a broad range of phenothiazine-based polymers as battery electrode materials, providing insight into the effect of π-interactions on battery performance, leading to design principles for highly functional phenothiazine-based polymers, and enabling the investigation of full cells. We observed that π-interactions are particularly expressed in “mono”-oxidized forms of poly(3-vinyl-N-methylphenothiazine) (PVMPT) and are enabled in the battery electrode due to the solubility of oxidized PVMPT in many carbonate-based liquid electrolytes. PVMPT dissolves during charge and is redeposited during discharge as a stable film on the positive electrode, however, still retaining half of its charge. This diminishes its available specific capacity to half of the theoretical value. We followed three different strategies to mitigate dissolution and inhibit the formation of π-interactions in order to access the full specific capacity for the one-electron process: Adjusting the electrolyte composition (type and ratio of cyclic vs. linear carbonate), encapsulating PVMPT in highly porous conductive carbons or cross-linking the polymer to X-PVMPT. All three strategies are excellently suited to pursue full-cell concepts using PVMPT or X-PVMPT as positive electrode material. The extent of π-interactions could also be modified by structural changes regarding the polymer backbone (polystyrene or polynorbornene) or exchanging the heteroatom sulfur in phenothiazine by oxygen in phenoxazine. By changing the molecular design and attaching electron-donating methoxy groups to the phenothiazine units, its second redox process can be reversibly enabled, even in carbonate-based electrolytes. Studies by us as well as others provided a selection of high-performing phenothiazine polymers. Their applicability was demonstrated as positive electrode in full cells of different configurations, including dual-ion battery cells using an inorganic or organic negative electrode, anion-rocking-chair cells as examples of all-organic batteries, or even an aluminum battery with a performance exceeding that of aluminum-graphite battery cells. In changing the design concept to conjugated phenothiazine polymers, a higher intrinsic semiconductivity can result, enabling the use of a lesser amount of the conductive carbon additive in the composite electrode. It also provides a handle to alter the optical properties of the polymers, for instance by designing donor–acceptor type conjugated polymers with visible-light absorption, where we demonstrated an application in a photobattery. This Account provides an overview of these findings, also in the context of other literature in the field. It highlights phenothiazine polymers as versatile electrode materials for next-generation batteries.

The four-parameter Klein-Hanley m-6–8 pair potential has been used to calculate simultaneously the viscosity η(T) and second virial coefficient (SVC) B(T) for 18 gases, including the rare gases Ne–Xe, the diatomic molecules D₂, N₂, O₂, F₂, Cl₂, and Br₂, and eight polyatomic molecules varying in complexity from CH₄ to C(CH₃)₄ over specified temperature ranges appropriate for each gas. The potential parameters m and γ are fully variable (in addition to ε, the well depth, and σ, the hard-sphere interaction distance) because the reduced collision integrals and SVCs, which are used to calculate η(T) and B(T), are expressed analytically as functions of of m, γ, and T. The four parameters are optimized by regression analysis, in which the calculated η(T) and B(T) are compared with the respective reference values. It is shown that, for the rare gases, N₂, O₂, F₂, CH₄, and CO₂, a linear correlation with unity slope exists between the m-6–8 ε parameter and D_e, the well depth obtained from ab initio calculations and from experiment, suggesting that such pair potentials should correspond with the actual depth of the isotropic potential energy curve. This relationship resolves the disparity in ε and σ values of the Lennard-Jones potential obtained from η(T) and B(T) data. The results of this study show that for all 18 gases, ε correlates with the exothermicity of dimer formation, calculated at a common reduced temperature of 0.7.

Although extensive literature exists on the depolymerization, fragmentation, and dehydration reactions occurring during cellulose pyrolysis, little is known about the secondary reactions involving dehydrated and fragmented oligomeric molecules that lead to the formation of highly modified oligomeric products in bio-oils and char. These secondary reactions are of significant practical importance. The highly dehydrated and modified dimers and trimers present in bio-oils are believed to act as coke precursors during hydrotreatment, while the larger oligomeric products contribute to char formation during pyrolysis. To bridge this knowledge gap, this study employs molecular dynamics simulations using the reactive force field (ReaxFF) to investigate the secondary reactions of dehydrated cellulose oligomers and the mechanisms driving heavy fraction formation. Postsimulation analysis identified over 400 reactions, proposed multiple reaction networks, and revealed key intermediates. To validate the modeling strategy, theoretical predictions were compared with experimental data obtained via direct insertion probe Fourier transform ion cyclotron resonance mass spectrometry (DIP FT-ICR MS) in the 87–1000 Da mass range. Probability distribution functions and molecular weight distribution analysis showed a 77% overlap between ReaxFF predictions and DIP FT-ICR MS data, confirming the reliability of the modeling strategy in forecasting fast pyrolysis behavior. Further validation was achieved through a van Krevelen diagram, which demonstrated that char fragments derived from ReaxFF simulations closely aligned with experimental data for cellulose char obtained at 400 °C. By integrating computational and experimental approaches, this study provides new insights into the secondary reactions of cellulose oligomers, highlights the role of key intermediates and water removal in these processes, and offers new opportunities for advancing selective biomass conversion technologies.

The sample-based quantum diagonalization (SQD) method shows great promise in quantum-centric simulations of ground state energies in molecular systems. Inclusion of solute–solvent interactions in simulations of electronic structure is critical for biochemical and medical applications. However, all of the previous applications of the SQD method were shown for gas-phase simulations of the electronic structure. The present work aims to bridge this gap by introducing the integral equation formalism polarizable continuum model (IEF-PCM) of solvent into the SQD calculations. We perform SQD/cc-pVDZ IEF-PCM simulations of methanol, methylamine, ethanol, and water in aqueous solution using quantum hardware and compare our results to CASCI/cc-pVDZ IEF-PCM simulations. Our simulations on ibm_cleveland, ibm_kyiv, and ibm_marrakesh quantum devices are performed with 27, 30, 41, and 52 qubits demonstrating the scalability of SQD IEF-PCM simulations.

Transthyretin (TTR) is a key transporter of the thyroid hormone thyroxine, and chemicals that bind to TTR, displacing the hormone, can disrupt the endocrine system, even at low concentrations. This study evaluates computational modeling strategies developed during the Tox24 Challenge, using a data set of 1512 compounds tested for TTR binding affinity. Individual models from nine top-performing teams were analyzed for performance and uncertainty using regression metrics and applicability domains (AD). Consensus models were developed by averaging predictions across these models, with and without consideration of their ADs. While applying AD constraints in individual models generally improved external prediction accuracy (at the expense of reduced chemical space coverage), it had limited additional benefit for consensus models. Results showed that consensus models outperformed individual models, achieving a root-mean-square error (RMSE) of 19.8% on the test set, compared to an average RMSE of 20.9% for the nine individual models. Outliers consistently identified in several of these models indicate potential experimental artifacts and/or activity cliffs, requiring further investigation. Substructure importance analysis revealed that models prioritized different chemical features, and consensus averaging harmonized these divergent perspectives. These findings highlight the value of consensus modeling in improving predictive performance and addressing model limitations. Future work should focus on expanding chemical space coverage and refining experimental data sets to support public health protection.

Neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.