Replacing cholesterol and PEGylated lipids with zwitterionic ionizable lipids in LNPs for spleen-specific mRNA translation.

ABSTRACT: The spleen is emerging as a key vaccination target. However, existing lipid nanoparticles (LNPs) primarily accumulate in the liver, limiting their efficacy in vaccine therapy. The cholesterol in current LNP formulations promotes their uptake by hepatocytes, while the polyethylene glycol-modified (PEGylated) lipids induce PEG immunogenicity, further reducing the efficacy in the setting of repeated administrations. We develop a three-component (ThrCo) LNP by replacing cholesterol and PEGylated lipids in Pfizer-BioNTech LNPs with zwitterionic pyridine carboxybetaine (PyCB) ionizable lipids (ILs), achieving ~70% lower liver accumulation and a 4.5-fold increase in spleen-specific mRNA translation. PyCB ILs enhance LNP hydrophilicity, stabilizing the outer membrane to compensate for cholesterol

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC12506999 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature