ACS biomaterials science & engineeringSep 14, 2026

Sugar-coated fat nanoparticles improve mRNA delivery to immune cells in the spleen

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 15, 2026

Abstract

Increasing the content of a mannose-conjugated lipid from 5% to 10% led to exclusive spleen localization of lipid nanoparticles.

Mannosylated lipid nanoparticles (LNP-PAM) were developed to enhance mRNA delivery to immune cells.
All formulations displayed uniform particle size and low variation in size distribution.
Higher levels of the mannose-conjugated lipid shifted the accumulation of LNPs from the liver to the spleen.
LNP-PAM showed improved mRNA delivery efficiency in macrophages compared to standard LNPs.
In vivo studies indicated increased mRNA expression in the spleen using LNP-PAM.
Flow cytometry results confirmed preferential uptake of LNP-PAM by macrophages and type-2 conventional dendritic cells.

Simplified

Targeted delivery of lipid nanoparticles (LNP) to immune organs remains challenging, and here we introduce a mannosylated spleen-targeted LNP (LNP-PAM) that integrates active and endogenous targeting to enhance mRNA delivery to antigen-presenting cells. A mannose-conjugated fifth lipid (PA-Mannose, PAM) was incorporated into spleen-targeted LNPs at varying molar ratios, followed by a systematic evaluation of physicochemical properties, in vitro transfection, in vivo biodistribution, cellular uptake, and mRNA expression. All formulations exhibited uniform particle size and low polydispersity, and increasing PAM content from 5% to 10% shifted LNP accumulation from the liver to the spleen, ultimately achieving exclusive spleen localization. LNP-PAM showed superior in vitro transfection in macrophages relative to conventional LNPs and higher in vivo mRNA expression in the spleen, with flow cytometry confirming preferential uptake by macrophages and type-2 conventional dendritic cells (cDC2) populations consistent with CD206-mediated endocytosis. The system maintained physicochemical stability after freeze-thaw and demonstrated minimal cytotoxicity. Together, these findings indicate that mannosylation enhances spleen-targeted mRNA delivery through receptor-mediated uptake by macrophages and dendritic cells without compromising formulation robustness, positioning LNP-PAM as a practical platform for selective immune organ delivery and RNA-based immunomodulation.