The immunomodulatory power of mesenchymal stem/stromal cell-derived extracellular vesicles in bone disorders: A comprehensive review.

Bones are not only mechanical structures but also highly active immunological organs. The bone marrow hosts hematopoietic, mesenchymal, and immune cells that continuously interact to coordinate bone remodeling, hematopoiesis, and systemic immune responses. Disruption of this osteoimmune network contributes to pathological conditions such as delayed fracture healing, osteoporosis, osteoarthritis, osteomyelitis, and other bone-destructive disorders. Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as key paracrine mediators and promising therapeutic candidates within this system. In this review, we summarize current knowledge on the biogenesis, composition, and characterization of MSC-EVs, and then focus on how they modulate macrophages, neutrophils, T and B cells, natural killer (NK) cells, and other stromal populations in the bone microenvironment. We discuss preclinical evidence across major bone disorders, including fracture repair, osteoporosis, osteoarthritis, osteonecrosis, periodontitis, and osteomyelitis, emphasizing the immunomodulatory mechanisms involved (e.g., regulation of M1/M2 balance, Th17/Treg ratios, neutrophil extracellular traps, and NK cell activity). Finally, we outline translational progress, including early clinical studies, manufacturing and potency-assay challenges, and outstanding questions that must be addressed to integrate MSC-EVs into future therapeutic strategies for bone disease.