bioRxiv : the preprint server for biologyNov 24, 2025

Negatively charged fats affect immune response to mRNA lipid nanoparticles and provide protection in a mouse model of multiple sclerosis

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Anionic lipid choices tuned mRNA-LNP immune targeting and produced a tolerizing DOPG formulation that suppressed disease in a mouse multiple sclerosis model.

Evidence

A preclinical formulation study tested 40 mRNA-LNP formulations for dendritic-cell delivery, innate activation, cytokine responses, and MOG-encoded DOPG LNP effects on neuroinflammation, T cell infiltration, and myelin morphology in a mouse model of multiple sclerosis.

Caveat

The protective result is preclinical and formulation-specific, with no human autoimmune-disease outcomes reported.

Simplified

The modularity of mRNA-lipid nanoparticle (mRNA-LNP) platforms has enabled their rapid adaptation from infectious disease vaccines to emerging applications in immune-mediated disorders. However, extending mRNA-LNPs to autoimmune and inflammatory diseases requires precise control over immune cell targeting and immunogenicity. Here, we systematically investigate how incorporating anionic lipids into LNPs modulates both immune cell tropism and innate immune activation. Using a library of 40 distinct LNP formulations, we demonstrate that anionic lipids enhance mRNA delivery to splenic dendritic cells, reduce early cellular markers of adjuvant activity and tune cytokine responses in a lipid-dependent manner. We identify formulations that retain pro-inflammatory adjuvant activity and others that promote tolerogenic responses. A lead formulation containing the anionic lipid DOPG selectively dampens innate activation and induces IL-10 production. When encoding the myelin antigen MOG, this LNP suppresses disease in a mouse model of multiple sclerosis, reducing neuroinflammation, T cell infiltration, and maintaining myelin morphology. These findings establish a framework for designing immune-targeted mRNA-LNPs with tunable immunogenicity and promote the development of antigen-specific tolerizing immunotherapies for autoimmune disease. 35-55