Aromatic Ionizable Lipids Enhance mRNA Delivery via Coordinating Multiple Mechanisms

Lipid nanoparticles (LNPs) have been extensively used for mRNA delivery and therapeutics, yet their delivery efficacy remains suboptimal. Advancing lipid chemistries and elucidating mechanisms of action offer avenues to enhance their efficacy. Here, we design a library of over 900 aromatic ionizable lipids and systematically study the aromatic incorporation in enhancing mRNA delivery via coordinating multiple mechanisms. Mechanistic investigations reveal that introducing aromatic groups significantly enhances the binding affinity between LNPs and mRNA, improving the encapsulation efficiency. Moreover, aromatic modification promotes membrane fluidity, facilitating superior cellular uptake and endosomal escape. During endosomal membrane remodeling, LNP dissociation and mRNA release occur simultaneously, enabling efficient cytosolic mRNA delivery. Collectively, aromatic incorporation supports multiple steps in the delivery process, resulting in substantially enhanced mRNA delivery efficacy in vivo. Notably, the top-performing candidate exhibits nearly an order-of-magnitude enhancement in delivery efficacy over FDA-approved SM-102 LNPs following both intravenous and intramuscular administration. This study not only presents a robust and efficient aromatic-derived LNP platform for mRNA delivery but also provides broader insights into the rational design and mechanistic understanding of ionizable lipids through the structural exploitation of aromatic functionalities.