Degradable cyclic amino alcohol ionizable lipids as vectors for potent influenza mRNA vaccines.

The next generation of mRNA vaccines must address several limitations, including enhancing vaccine potency and reducing toxicity. Here we develop a class of degradable, cyclic amino ionizable lipids via sequential combinatorial chemistry and rational design. Lipid nanoparticles (LNPs) formulated with the top-performing ionizable lipid, AMG1541, elicited similar protective neutralization antibody titres against an H3 influenza antigen when compared with the FDA-approved ionizable lipid SM-102 at a 100-fold lower dose, with enhanced clearance in vivo. AMG1541 mRNA LNPs substantially reduced expression in the liver following intramuscular injection, mitigating the associated toxicity. We also observed improved mRNA delivery to antigen-presenting cells at the injection site and the draining lymph node, leading to stronger germinal centre reactions. Structure-activity relationship studies suggest that cyclic headgroups and β-amino alcohols facilitate interactions with the mRNA backbone and enhance endosomal escape. The formulations developed here significantly enhance the potency of mRNA vaccines, and our structural insights may guide the development of next-generation vaccine delivery systems.