ACS nanoJul 27, 2026

Understanding the Roles of Different Parts in mRNA Lipid Nanoparticles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 28, 2026

Abstract

Ionizable lipids are critical for mRNA delivery efficacy in lipid nanoparticles (LNPs).

Cholesterol is essential for efficient delivery of mRNA to the liver but not necessary for delivery to other organs.
Phospholipid does not appear to influence the targeting of mRNA delivery to specific organs.
LNPs without phospholipid significantly reduce inflammation.
Removal of PEG-lipid affects particle size, leading to LNPs with a preference for targeting the spleen.
Each lipid component plays a distinct role in the behavior and effectiveness of LNPs in delivering mRNA.

Simplified

Lipid nanoparticles (LNPs) have represented a leading platform for mRNA delivery and therapeutics. While extensive studies have focused on optimizing ionizable lipids, the specific roles of helper lipids such as cholesterol, phospholipid, and polyethylene glycol lipid (PEG-lipid) remain relatively poorly understood. To elucidate the distinct contributions of individual lipid components, we reengineer LNP formulations by selectively removing each lipid component, especially helper lipids, to systematically analyze their effects on physicochemical properties, in vivo mRNA delivery, and inflammatory responses. Results reveal that ionizable lipid plays a critical role in mRNA delivery efficacy. Cholesterol is essential for efficient liver-targeted delivery but dispensable for extrahepatic delivery. Phospholipid is not directly associated with organ tropism, whereas phospholipid-free LNPs significantly alleviate inflammation. PEG-lipid influences particle size, with PEG-lipid-free LNPs exhibiting preferential spleen tropism. This study comprehensively demonstrates the important roles of each lipid component in determining the in vivo fate of LNPs, guiding the rational design of next-generation LNP-based mRNA delivery systems.