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

📖 Top 20% JournalJul 8, 2025Biomaterials science

Special ionizable lipids with ring-shaped amine heads help deliver mRNA specifically to the spleen

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Abstract

Twenty-five ionizable lipid molecules were synthesized for nucleic acid delivery, with W19 showing highly selective mRNA delivery to the spleen.

Lipid nanoparticles (LNPs) are a key platform for delivering nucleic acids.
Targeting non-hepatic organs with LNPs presents challenges.
Ionizable lipids were designed to enhance the properties of LNPs for organ-specific delivery.
The Ugi four-component reaction was utilized to create diverse ionizable lipid structures.
The synthesized W19 LNPs demonstrated effective mRNA delivery specifically to the spleen after intravenous administration.

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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 lipidsan 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. via

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