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

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 MOG27-63 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.