LAUSR

Lipid nanoparticles (LNPs) have proven a successful platform for the delivery of nucleic acid (NA)‐based therapeutics and vaccines, with the ionizable lipid component playing a key role in modulating potency and tolerability. Here, a library of 16 novel ionizable lipids is screened hypothesizing that short, branched trialkyl hydrophobic domains can improve LNP fusogenicity or endosomal escape, and potency. LNPs formulated with the top‐performing trialkyl lipid (Lipid 10) encapsulating transthyretin siRNA elicit significantly greater gene silencing and are better tolerated than those with the benchmark Onpattro lipid DLin‐MC3‐DMA. Lipid 10 also demonstrates superior liver delivery of mRNA when compared to other literature ionizable lipids, is well tolerated, and successfully repeat‐doses in nonhuman primates. In a prime‐boost hemagglutinin rodent vaccine model, intramuscular administration of Lipid‐10 LNP elicits comparable or better antibody titers to the SM‐102 and ALC‐0315 lipid compositions used in the U.S. Food and Drug Administration approved mRNA COVID vaccines. These data suggest that Lipid 10 is a particularly versatile ionizable lipid, well‐suited for both systemic therapeutic and intramuscular vaccine applications and able to successfully deliver diverse NA payloads.