Anionic lipids modulate mRNA-lipid nanoparticle immunogenicity and confer protection in a mouse model of multiple sclerosis

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 _35-55 , 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.