Mannose-Conjugated Cholesterol Containing Lipid Nanoparticles for Active Targeted mRNA Delivery to Liver Sinusoidal Endothelial and Kupffer Cells

Sep 11, 2025Bioconjugate chemistry

Mannose-coated cholesterol lipid particles for targeted mRNA delivery to liver filtering and immune cells

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Mannosylated lipid nanoparticles enhanced uptake into liver sinusoidal endothelial cells and Kupffer cells over hepatocytes following intravenous administration in mice.

Lipid nanoparticle delivery of mRNA is influenced by serum ApoE binding, limiting effectiveness in nonhepatocyte liver diseases.
Incorporating mannose-conjugated cholesterol into lipid nanoparticles may improve targeting to specific liver cell types.
Mannosylated lipid nanoparticles showed significantly greater uptake in liver sinusoidal endothelial cells and Kupffer cells compared to hepatocytes.
Uptake correlated with the expression of mannose receptors (CD206) in LSECs and Kupffer cells.
Reducing the acyl chain length in PEG lipids could enhance the activity and selectivity of lipid nanoparticles by increasing accessible mannose on their surface.

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Lipid nanoparticle (LNP) delivery of mRNA to specific cell types is a necessary task for the development of safe and effective medicines. LNP delivery to the liver is largely driven by the binding of serum ApoE to the LNP surface, followed by subsequent uptake in LDL receptor (LDL-R)-expressing hepatocytes, thereby reducing their utility in nonhepatocyte liver diseases. Herein, we developed an active targeting strategy to overcome this limitation by incorporating mannose-conjugated cholesterol into LNPs. Since cholesterol comprises about half of all molecules in LNPs, we reasoned that it could serve as a scaffold for active targeting. Mannosylated LNPs enhance uptake into liver sinusoidal endothelial cells (LSECs) and Kupffer cells over hepatocytes following intravenous administration in mice. This process correlated with the expression of mannose receptors (CD206) in LSECs and Kupffer cells, where significantly greater LNP uptake and functional mRNA delivery occurred in CD206cells. Higher activity and selectivity could be endowed by reducing the hydrophobic acyl chain length in poly(ethylene glycol) (PEG) lipids to induce faster PEG shedding in systemic circulation and increase LNP surface-accessible mannose, thereby increasing binding interactions with mannose receptors on CD206cells and subsequent LNP uptake. The results establish that cholesterol can be employed as a ligand carrier in LNPs for enriching mRNA delivery to specific cells. We anticipate that this general strategy of cholesterol modification can be extended to other ligands and cell types in the future. + + in vivo