Materiomically Designed Polymeric Vehicles for Nucleic Acids: Quo Vadis?

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.