Home Products Cited in Publications Worldwide Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo
Xuexiang Han; Mohamad-Gabriel Alameh; Ningqiang Gong; Lulu Xue; Majed Ghattas; Goutham Bojja; Junchao Xu; Gan Zhao; Claude C. Warzecha; Marshall S. Padilla; Rakan El-Mayta; Garima Dwivedi; Ying Xu; Andrew E. Vaughan; James M. Wilson; Drew Weissman; Michael J. Mitchell
DOI:10.1038/s41557-024-01557-2 PMID:38982196
Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly afecting biodistribution, cellular uptake, endosomal escape and transfection efciency. However, the laborious synthesis of cationic lipids limits the discovery of efcacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identifcation of a tail-like amine-ring-alkyl aniline that generally afords efcacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.