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Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy. [ABSTRACT FROM AUTHOR]