Unsaturated, Trialkyl Ionizable Lipids are Versatile Lipid‐Nanoparticle Components for Therapeutic and Vaccine Applications

• DOI: 10.1002/adma.202209624
• Publication Date: 2023-01-21T10:43:44Z
• Authors: Kieu Lam; Ada Leung; Alan Martin; Mark Wood; Petra Schreiner; Lorne Palmer; Owen Daly; Wenchen Zhao; Kevin McClintock; James Heyes
• Keywords: Lipid A

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