Ugi-reaction-derived ionizable lipids with cyclic tertiary amine heads enable spleen-targeted mRNA delivery.

Lipid nanoparticles (LNPs) have become an important platform for nucleic acid delivery. However, LNP-mediated delivery to non-hepatic organs and specific cell types remains a non-negligible challenge. As a key component of LNPs, ionizable lipids were rationally designed to adjust the LNPs properties to achieve organ-targeted delivery. The use of the Ugi four-component reaction (Ugi-4CR) as a one-pot multicomponent synthesis strategy to construct ionizable lipid molecules offers advantages, as it enables multidimensional structural diversity of ionizable lipids. We use isocyanides with cyclic tertiary amine substituents to construct ionizable lipids via an Ugi one-pot reaction. Twenty-five ionizable lipid molecules (W1-W25) containing different cyclic tertiary amine hydrophilic heads, linkers, and hydrophobic tails were synthesized. The W19 LNPs exhibited highly selective mRNA delivery to the spleen upon intravenous administration.