Optimized Lipid Nanoparticles with Tail‐Modified Ionizable Lipids for Safer mRNA Delivery
ABSTRACT Despite the growing importance of lipid nanoparticles (LNPs) in mRNA therapeutics, current ionizable lipids, which comprise an ionizable head group, a linker, and hydrophobic tails that collectively govern the delivery behavior, exhibit dose‐limiting toxicity and suboptimal efficiency. Hydrophobic tail chemistry has been implicated in these limitations; however, a systematic structure–activity relationship (SAR) analysis is lacking. In this study, the authors synthesized a 56‐member library of tail‐modified ionizable lipids with biodegradable disulfide linkages and variations in chain length and branching. Systematic SAR evaluation revealed that hydrophobic tail architecture critically determines endosomal escape, biocompatibility, and mRNA translation efficiency. Optimized LNPs delivered mRNA with potent efficacy and markedly reduced cytotoxicity, lower cytokine induction, and balanced Th1/Th2 immune activation in a nonhuman primate model. The findings establish the first comprehensive SAR framework linking tail chemistry to ionizable lipid function, offering molecular design principles for next‐generation LNPs and enabling the development of safer and more effective mRNA‐based vaccines and therapeutics.