Development of multifunctional block copolymers for the delivery of nucleic acid vaccines

Abstract

Plasmid DNA (pDNA) and messenger RNA (mRNA) vaccines hold significant potential as versatile, safe, and cost-effective technologies for the treatment of cancer and infectious diseases. However, clinical applications are currently limited by poor immunogenicity attributable to limitations in nucleic acid delivery efficacy. Synthetic nonviral delivery vectors represent a promising approach to improving vaccine potency through the enhancement of gene transfection. This dissertation describes the development of multifunctional block copolymers as delivery platforms for nucleic acid vaccines. Polymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, a technique enabling the facile production of well-defined block copolymers with complex architectures. First, a series of block copolymers composed of discrete cationic, endosomolytic, and hydrophilic segments was evaluated for mRNA delivery. Polymer designs producing highly stable mRNA polyplexes were associated with high in vitro transfection efficiencies and successfully delivered antigen-encoding mRNA to dendritic cells (DCs) for T cell activation. Second, glycopolymer micelles incorporating an endosomolytic core and mannosylated corona for DC targeting were assessed for pDNA vaccine delivery efficacy in mice. Compared to uncomplexed pDNA and untargeted micelles, mannosylated micelles exhibited enhanced uptake by DCs in lymph nodes and elicited increased antigen-specific antibody responses. Overall, these findings demonstrate the potential of multifunctional RAFT-based polymers for improving the delivery of nucleic acid therapeutics for vaccination strategies.