Unsaturated, Trialkyl Ionizable Lipids are Versatile LNP Components for Therapeutic and Vaccine Applications.

Lipid nanoparticles (LNP) 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, we screened a library of 16 novel ionizable lipids hypothesizing that short, branched trialkyl hydrophobic domains would improve LNP fusogenicity or endosomal escape, and potency. LNPs formulated with the top-performing trialkyl lipid (Lipid 10) encapsulating transthyretin siRNA elicited significantly greater gene silencing and were better tolerated than those with the benchmark Onpattro ® lipid DLin-MC3-DMA. Lipid 10 also demonstrated superior liver delivery of mRNA when compared to other literature ionizable lipids, was well tolerated, and successfully repeat dosed in non-human primates. In a prime-boost hemagglutinin (HA) rodent vaccine model, intramuscular administration of Lipid-10 LNP elicited comparable or better antibody titers to the SM-102 and ALC-0315 lipid compositions used in the FDA-approved mRNA COVID vaccines. Our 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. This article is protected by copyright. All rights reserved.