Multivalent Peptide-Functionalized Bioreducible Polymers for Cellular Delivery of Various RNAs

RNA-based therapeutics have garnered tremendous attention due to their potential to revolutionize protein replacement therapies, immunotherapy, and treatment of genetic disorders. The lack of safe and efficient RNA delivery methods has significantly hindered the clinical translation and widespread application of RNA-based therapeutics. With differing sizes and structures of therapeutic RNA molecules, a critical challenge of the field is to develop RNA delivery systems that accommodate these variations while retaining high biocompatibility and efficacy. In this study, we developed a series of multivalent peptide-functionalized bioreducible polymers (MPBP) as a safe and efficient delivery vehicle derived from a core polymer backbone for various RNA species. The facile synthesis of MPBPs from a single polymer backbone provides access to numerous polymers with diverse architectures that enable cellular delivery of different RNA cargos. Postfunctionalization with multifunctional peptides enables strong RNA complexation, enhanced cellular uptake, and facilitates endosomal escape of cargo. The high delivery efficiency and low cytotoxicity for various RNA-MPBP nanoparticles in multiple cell lines demonstrates that the MPBP approach is a novel promising vector strategy for future RNA delivery systems.