Tetrahydropyrimidine Ionizable Lipids for Efficient mRNA Delivery

Lipid nanoparticles (LNPs) have emerged as an effective and promising technology for messenger RNA (mRNA) delivery, offering a potential solution to physiological barriers and providing an alternative approach to gene therapy without the drawbacks associated with viral delivery. However, efficiently delivering mRNA remains a significant challenge in nucleic acid-based therapies due to the limitations of current LNP platforms in achieving optimal endosomal escape and mRNA release, which largely relies on finding a suitable ionizable lipid. Additionally, the synthesis of these ionizable lipids involves multiple chemical reactions, often making the process time-consuming and difficult to translate. In this study, we employed a facile, catalyst-free, and versatile one-pot multicomponent reaction (MCR) to develop a library of ionizable lipids featuring a pharmacologically significant tetrahydropyrimidine (THP) backbone, tailored for enhanced mRNA delivery. A library of 26 THP ionizable lipids was systematically synthesized in just 3 h and formulated with luciferase mRNA for initial