BiomaterialsSep 10, 2025

How Phospholipids Help Lipid Nanoparticles Target Specific Organs

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

PL-containing SORT LNPs significantly increase protein expression after intramuscular administration in mice.

Enrichment of phospholipids enhances cellular transfection efficiency by promoting membrane fusion and endosomal escape.
Moderate inclusion of phospholipids is optimal for intravenous delivery of LNPs.
PL modulation leads to distinct structural changes in LNPs, potentially affecting the adsorption of plasma proteins.
The protein corona formed around LNPs is important for directing their biodistribution to specific organs.
Understanding the role of phospholipids is essential for developing more effective mRNA delivery systems.

Simplified

Modular lipid nanoparticles (LNPs) are a promising platform to deliver mRNA to various tissues and cells. Optimization of LNPs for hepatic and extrahepatic tissues often involves substitution of helper lipids or addition of novel lipids not found in conventional four-component LNPs. Among the lipids that comprise LNPs, the functional contributions of phospholipids (PLs) in selective organ targeting (SORT) LNPs remain poorly understood. In this study, we systematically evaluate the roles of PLs within SORT LNPs. Our results demonstrate that PL enrichment enhances cellular transfection efficiency by increasing membrane fusion and endosomal escape. In vivo, we observe that PL-containing SORT LNPs significantly increase protein expression following intramuscular administration in mice, whereas moderate PL inclusion is optimal for intravenous delivery. Cryo-electron microscopy reveals that PL modulation induces distinct morphological rearrangements in LNP structure, which may influence the selective adsorption of plasma proteins, an essential factor in endogenous targeting mechanisms. These findings highlight the fundamental role of PLs in supporting intracellular delivery and guiding organ-specific biodistribution through protein corona formation. A deeper understanding of the structural and functional impact of lipid components, especially PLs, will be crucial for the rational design of next-generation mRNA delivery systems with improved efficacy and precision.

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How Phospholipids Help Lipid Nanoparticles Target Specific Organs

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