Autoantigen mRNA‐LNP Vaccination Drives Therapeutic Efficacy in Preclinical Models for Autoimmunity

ABSTRACT Autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes (T1D) lack therapies that induce durable, antigen‐specific immune tolerance. We investigated whether mRNA lipid nanoparticles (LNPs) encoding disease‐relevant autoantigens could re‐establish immune homeostasis in preclinical models. While mRNA‐LNP microbial vaccines evoke strong effector immune responses, we show that both systemic and intramuscular delivery of MOG _27‐63 mRNA‐loaded LNPs attenuated disease severity in experimental autoimmune encephalomyelitis (EAE). Antigen‐specific protection was similarly observed in a T1D adoptive transfer model. Therapeutic efficacy achieved using immunostimulatory LNPs challenges the current assumption that tolerogenic mRNA vaccines require immune‐silent LNPs. Furthermore, divergent outcomes between autoantigens and irrelevant antigens suggest that antigen identity determines whether mRNA‐LNPs promote immune tolerance or activation. Mechanistically, optimized LNPs efficiently targeted antigen‐presenting cells (APCs) in the liver and spleen. This promoted a homeostatic APC phenotype and a hyporesponsive CD4 ⁺ T cell phenotype without inducing regulatory T cells (Tregs). Therefore, autoantigen mRNA was co‐delivered with “immunoregulatory” mRNAs encoding cytokines (IL‐2 mutein) or chemokines (CCL1) known to enhance Treg expansion and recruitment. This co‐delivery further improved clinical outcomes in EAE. Together, these findings demonstrate that systemic and intramuscular treatment with mRNA‐LNPs encoding autoantigens alongside immunoregulatory molecules represents a promising strategy for antigen‐specific immunotherapy in autoimmune diseases.