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Autoimmune diseases pose a significant challenge due to their complex pathogenesis and rising prevalence. Traditional therapies are often limited by systemic side effects, immunosuppression, and lack of long-term efficacy. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory properties, primarily through the secretion of extracellular vesicles (EVs), which are now recognized as potent mediators of immune regulation. MSC-derived EVs carry bioactive molecules such as microRNAs, proteins, and lipids that influence key immune pathways, making them a promising therapeutic avenue for autoimmune diseases. This review critically examines the immunomodulatory mechanisms of MSC-derived EVs, focusing on their role in regulating T cells, B cells, and macrophages, which are central to autoimmune pathology. We explore recent preclinical and clinical studies that highlight the ability of MSC-derived EVs to reduce inflammation, promote immune tolerance, and restore tissue homeostasis in autoimmune settings. Furthermore, we discuss the advantages of EV-based therapy over MSC-based therapies, including improved safety profiles, lower immunogenicity, and scalability for clinical application. By evaluating the current landscape of MSC-derived EV research, we identify key gaps and propose innovative strategies to optimize EVbased therapies for autoimmune diseases. These strategies include engineering EVs to enhance their specificity and therapeutic efficacy, as well as integrating them with biomaterials for targeted delivery. Our review aims to provide a forward-looking perspective on the potential of MSC-derived EVs as a novel therapeutic approach, moving beyond traditional cell-based therapies to offer more precise and personalized treatment options for autoimmune diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)