(78d) Zwitterionic Poly(carboxybetaine) Containing Lipid Nanoparticles Enable Efficient mRNA Transfection

Poly(carboxybetaine) (PCB) is a super-hydrophilic polymer known for its robust stealth properties. In various biomedical applications, it has become a promising alternative to poly(ethylene) glycol (PEG), which is currently used in the lipid nanoparticle (LNP) for RNA delivery. PEG-lipid is an indispensable component which is maintaining particle stability and prolonging its in vivo half-life. However, it was recently associated with concerns related to efficacy and immunogenicity. In this work, we designed novel PCB-lipids to replace PEG counterparts in lipid nanoparticles (LNPs) for mRNA delivery. In various cell lines, PCB-LNP performed significantly higher transfection efficacy than PEG-LNP. We also validated the superior efficacy of PCB-LNP in various applications including ex vivo editing in primary cells and in vivo vaccines. Structural characterization revealed that the enhanced efficacy attributed to the better lipid fusogencitiy of PCB-LNPs, which led to more potent endosomal escape ability. Finally, PCB-LNPs demonstrated better safety profile compared to PEG-LNPs by evaluating the cytokine secretion from human peripheral mononuclear cells (PBMCs) and liver toxicity panel. In conclusion, through comprehensive structural and biological investigations, we demonstrated that PCB-LNPs emerge as a highly promising alternative to PEG-LNPs, offering enhanced potency and safety as carriers for RNA delivery in clinical applications.