Molecular therapy. Nucleic acidsJan 16, 2026

Delivering mRNA to the spleen using long-chain PEG lipids at low levels boosts immune response against melanoma

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A low-ratio long-chain PEGylated lipid formulation redirected mRNA lipid nanoparticles toward the spleen and strengthened antitumor immune activity in a melanoma model.

Evidence

This LNP engineering and preclinical in vivo study varied PEG-lipid chain length and molar ratio, identifying 0.75% mol DSG-PEG LNPs that enhanced spleen accumulation, dendritic-cell activation, antigen-specific CD4 T-cell expansion, and B16-OVA melanoma tumor inhibition.

Caveat

The antitumor result is from an engineered mouse melanoma model, and the abstract does not establish human efficacy or safety.

Simplified

Lipid nanoparticles (LNPs) are pivotal for mRNA delivery, yet predominant hepatic accumulation limits their therapeutic application in immunologically active sites like the spleen. Engineering LNPs for splenic mRNA delivery is therefore essential for advancing mRNA-based immunotherapies. Here, we rationally designed a series of LNPs by modulating the alkyl chain length of PEGylated lipids (fast-shedding C14 DMG-PEG vs. slow-shedding C18 DSG-PEG) and their molar ratios (0.75% and 1.5%). This systematic variation precisely controlled nanoparticle physicochemical properties and protein corona composition. Among these formulations, DSG-PEG LNPs at 0.75% mol exhibited the largest size (∼170 nm by DLS; ∼60 nm core by cryo-EM) and a distinct protein corona. Notably, this DSG-PEG 0.75% mol formulation demonstrated significantly enhanced selective spleen accumulation and efficient mRNA delivery. Furthermore, the optimized LNP potently activated dendritic cells, expanded antigen-specific CD4T cell populations, and significantly inhibited tumor growth in a B16-ovalbumin (OVA) melanoma model. Collectively, our results establish a rational strategy via precise PEGylated lipid engineering to redirect LNP biodistribution from the liver to the spleen. These findings validate the spleen as a critical target for mRNA vaccines and provide a versatile platform for next-generation cancer immunotherapies. in vivo +