Anti‐Inflammatory Macrophage‐Derived Exosomes Modified With Self‐Antigen Peptides for Treatment of Experimental Autoimmune Encephalomyelitis

Abstract Current treatments for autoimmune diseases often involve broad‐acting immunosuppressants, which carry risks such as infections and malignancies. This study investigates whether exosomes derived from anti‐inflammatory macrophages (AE) and decorated with myelin oligodendrocyte glycoprotein (MOG) peptide (AE/M) can induce immune tolerance in autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis, serves as the autoimmune disease model. Exosomes derived from myoblasts or fibroblasts are also modified with MOG peptides for comparison. Unlike their myoblast or fibroblast counterparts, exosomes from anti‐inflammatory macrophages demonstrate a targeted capacity toward antigen‐presenting cells. Moreover, AE/M uniquely promotes the differentiation of dendritic cells (DC) into a tolerogenic phenotype. When splenocytes are treated with AE/M, an increased population of tolerogenic DC (tolDC) is observed, even under proinflammatory stimuli. Subcutaneous administration of AE/M in the EAE mouse model results in MOG peptide‐specific immune tolerance and preserves motor coordination. In contrast to treatments with fibroblast‐ or myoblast‐derived exosomes modified with MOG peptides, AE/M treatment provides complete protection from EAE in mice. These findings highlight the potential of self‐antigen modified AE as a versatile and adaptable nanoplatform for the treatment of various autoimmune diseases.