Stem cell-derived extracellular vesicles as immunomodulatory agents: targeting pathological crosstalk in systemic lupus erythematosus and multiple sclerosis.

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immune-mediated diseases characterized by overlapping clinical presentations and shared immunoregulatory pathways. Both conditions involve dysregulated immune cell activation, autoantibody production, cytokine imbalance, compromised blood-brain barrier (BBB), and mechanisms that establish self-perpetuating cycles that drive neuroinflammatory cascades, demyelination, and tissue injury. Stem cell-derived extracellular vesicles (SC-EVs) efficiently deliver and protect bioactive cargo, notably key immunoregulatory molecules including microRNAs (miRNAs) and proteins, from enzymatic degradation through their bilayer membrane structure, facilitating intercellular communication and immune modulation. Preclinical studies in animal models of SLE and experimental autoimmune encephalomyelitis (EAE, the standard MS model) have demonstrated that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) modulate immune responses by suppressing pro-inflammatory mediators, enhancing anti-inflammatory signaling, promoting tissue repair, and conferring neuroprotection. Accumulating evidence suggests that the functional cargo of MSC-EVs targets key pathogenic processes in both diseases, including immune cell polarization, cytokine regulation, and tissue regeneration. This review examines the convergent immunomodulatory effects and mechanisms of SC-EVs in SLE and MS, highlighting their potential as cell-free immunotherapeutic agents for mitigating autoimmune-mediated damage. This review highlights the synergistic role of microRNA-146a-5p (miR-146a-5p) and microRNA-21-5p (miR-21-5p) in reprogramming immune responses and the context-dependent regulation of the hypoxia-inducible factor-1α (HIF-1α) axis in tissue repair.