A tolerogenic mRNA-LNP vaccine alleviates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Current non-specific immunosuppressive therapies carry risks of infection and malignancy. Antigen-specific tolerance induction presents a promising alternative. Here, we developed a messenger RNA-lipid nanoparticle (mRNA-LNP) vaccine (LiH-LNPs) encoding a tandem fusion of epitopes from three MS-associated myelin antigens. LiH-LNPs alleviated inflammatory infiltration and demyelination in experimental autoimmune encephalomyelitis (EAE). Single-cell RNA sequencing revealed that LiH-LNPs reshaped the spinal cord microenvironment toward inflammation resolution by reducing the abundance and inflammatory activity of infiltrating myeloid cells and activated microglia, inducing apoptosis of encephalitogenic T cells while increasing regulatory T (Treg) cell abundance and suppressive activity. These findings provide mechanistic insights into antigen-specific immunotherapy for MS and highlight the potential application of mRNA vaccine-based antigen-specific therapy for autoimmune diseases.