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We herein developed a tolerogenic nanovaccine and tested it an animal model of multiple sclerosis. The nanovaccine was constructed to deliver the self-antigen, MOG peptide, and dexamethasone on an abatacept-modified polydopamine core nanoparticle (AbaLDPN-MOG). AbaLDPN-MOG could target dendritic cells and undergo endocytosis followed by trafficking to lysosomes. AbaLDPN-MOG blocked the interaction between CD80/CD86 and CD28 in antigen-presenting cells and T cells, leading to decreased interferon gamma secretion. The subcutaneous administration of AbaLDPN-MOG to mice yielded significant biodistribution to lymph nodes and, in experimental-autoimmune encephalomyelitis (EAE) model mice, increased the integrity of the myelin basic sheath and minimized the infiltration of immune cells. EAE mice were treated with AbaLDPN-MOG before or after injection of the autoantigen, MOG. Pre-immunization of AbaLDPN-MOG before the injection of MOG completely blocked the development of clinical symptoms. Early treatment with AbaLDPN-MOG at 3 days after injection of MOG also completely blocked the induction of symptoms. Notably, treatment of EAE symptom-developed mice with AbaLDPN-MOG significantly alleviated the symptoms, indicating that the nanovaccine had therapeutic effects. Although we used AbaLDPN for MOG peptide delivery in the EAE model, the concept of AbaLDPN can be widely applied for the prevention and alleviation of other autoimmune diseases. This article is protected by