Biodegradable Poly(β-amino amide)s Enable Efficient RNA Delivery and Spleen Targeting

Abstract

RNA therapeutics are emerging as transformative modalities in clinical applications and have become a key area in life science research. While lipid nanoparticles (LNPs) have become the leading platform for RNA delivery in preventive and therapeutic products, they still face significant challenges in achieving efficient extrahepatic delivery and maintaining long term shelf stability. Here we report the development of a series of biodegradable poly({beta}-amino amide) (PBAA) polymers, detailing their design, synthesis, and performance as gene delivery vehicles both in vitro and in vivo. These cationic polymers, featuring interspersed trialkylamine motifs, provide a readily tunable functional handle and facilitate complexation with gene cargo. The redox-sensitive disulfide motifs introduce a redox-responsive decomposition pathway for the polymer backbone, triggering cargo release during intracellular delivery. The results herein demonstrate that these polymers offer remarkable efficiency in encapsulating and delivering translation-competent cargos, including mRNA and CRISPR-Cas based gene editing tools. Notably, a dodecyl modified PBAA transporter has achieved over 97% gene editing efficiency in vitro, and over 97% spleen-targeting selectivity in a murine model. Additionally, it produces stable nanoparticles that maintain their physicochemical properties at 4 {degrees}C for up to two weeks without addition of excipients such as PEG, offering a cost-effective solution for RNA therapeutics supply chains. As the transformative impact of RNA and other nucleic acids continues to build within the pharmaceutical industry and beyond, it is imperative that the supporting technologies evolve in stride to maximize said impact. The tunable and biodegradable PBAA polymer designs presented herein are illustrative examples of how high-level functional performance can be acheived in conjunction with the critical targeting, formulation, and operational simplicity needed of state-of-the-art transfection and delivery technologies.