Materiomically Designed Polymeric Vehicles for Nucleic Acids: Quo Vadis?

Abstract

Despite rapid advances in molecular biology, particularly in site-specific genome editing technologies, such as CRISPR/Cas9 and base editing, financial and logistical challenges hinder a broad population from accessing and benefiting from gene therapy. To improve the affordability and scalability of gene therapy, we need to deploy chemically defined, economical, and scalable materials, such as synthetic polymers. For polymers to deliver nucleic acids efficaciously to targeted cells, they must optimally combine design attributes, such as architecture, length, composition, spatial distribution of monomers, basicity, hydrophilic−hydrophobic phase balance, or protonation degree. Designing polymeric vectors for specific nucleic acid payloads is a multivariate optimization problem wherein even minuscule deviations from the optimum are poorly tolerated. To explore the multivariate polymer design space rapidly, efficiently, and fruitfully, we must integrate parallelized polymer synthesis, high-throughput biological screening, and statistical modeling. Although materiomics approaches promise to streamline polymeric vector development, several methodological ambiguities must be resolved. For instance, establishing a flexible polymer ontology that accommodates recent synthetic advances, enforcing uniform polymer characterization and data reporting standards, and implementing multiplexed in vitro and in vivo screening studies require considerable planning, coordination, and effort. This contribution will acquaint readers with the challenges associated with materiomics approaches to polymeric gene delivery and offers guidelines for overcoming these challenges. Here, we summarize recent developments in combinatorial polymer synthesis, high-throughput screening of polymeric vectors, omics-based approaches to polymer design, barcoding schemes for pooled in vitro and in vivo screening, and identify materiomics-inspired research directions that will realize the long-unfulfilled clinical potential of polymeric carriers in gene therapy.

An interpretable machine learning framework for modelling macromolecular interaction mechanisms with nuclear magnetic resonance

“…The impact of polymer molecular weight on mucoadhesion is an ongoing area of research, given confounding reports of increasing molecular weight being in some cases an enhancer of mucoadhesion, yet in others reducing it. 32,47 The influence that polymer molecular weight exerts on resulting interactions is unclear, 15 therefore it is unlikely to be a standalone predictor, though it provides a proxy measure for physical macromolecular structural influences on proton level interaction.…”

Data-Driven Design of Polymer-Based Biomaterials: High-throughput Simulation, Experimentation, and Machine Learning

“…69 Overall, as flow-based polymerization is amenable to myriad reactions with fine control, it can enhance the throughput of polymer synthesis. 29,70 2.1.2. Characterization.…”

“…In other demonstrations of substantial polymer throughput, Kumar et al used a parallel synthesizer to carry out RAFT polymerization of methacrylate in batches of 12, and Reis et al utilized continuous, flow-based RAFT polymerization, producing methacrylate-based copolymers in batches of 30 . Overall, as flow-based polymerization is amenable to myriad reactions with fine control, it can enhance the throughput of polymer synthesis. , …”

“…Polymers exhibit wide-ranging properties that make them attractive for myriad technologies. − In biomaterials, polymers (both biopolymers as well as synthetic ones) can feature chemical functionalities that engender biomemetic and biointerfacing properties. − Inspired by the biological complexity present in DNA and proteins, sequence-defined polymers have significant theoretical interest and promise for medicine, nanotechnology, and information storage, − but even random copolymers, with the right balance of hydrophobic, polar, and charged electrostatic interactions, can mimic the range of conformational behaviors observed in proteins. − Synthetic copolymers can also be tailored to interface with specific proteins, modulating their enzymatic activity or protecting them in denaturing environments. − As the synthetic toolbox for polymers expands, ,,,,, so too does their capacity to enhance or mimic biological functions, giving rise to applications in catalysis, − drug delivery, − biosensors, tissue engineering, and more.…”

Microstructure and Water Vapor Barrier Performance of Organic‐Bridged Polysilsesquioxane/Carbon Quantum Dots Composite Coatings

“…Then, many strategies were proposed to enhance the water vapor barrier properties of polymeric coatings. Among them, the incorporation of fillers into polymeric coatings was obviously efficient and the commonly used fillers for polymer are nanoparticles [ 18,19 ] and nanoplates. [ 20,21 ] According to the Nielsen model, fillers with higher aspect ratio were considered to be more effective in enhancing the water vapor barrier ability of composite coatings.…”