Bridging Osteoimmunology and Regenerative Therapy: The Role of MSCs and Extracellular Vesicles

Bone homeostasis and regeneration depend on tightly regulated interactions between skeletal cells and the immune system within the bone microenvironment. Disruption of this crosstalk by ageing, chronic inflammation, or systemic disease contributes to osteoporosis, inflammatory bone loss, and impaired fracture healing. Osteoimmunology has reframed bone biology as an immune-regulated process, highlighting mesenchymal stem cells (MSCs) as central coordinators of bone-immune communication. Beyond their differentiation capacity, MSCs act primarily through paracrine mechanisms, releasing a secretome composed of soluble factors and extracellular vesicles (EVs) that modulate immune responses, regulate osteoblast and osteoclast activity, promote angiogenesis, and support extracellular matrix remodelling. MSC-derived EVs have emerged as key nanoscale mediators that transfer bioactive cargo to target cells in a context-dependent manner, enabling precise regulation of osteoimmune processes. This review summarises current knowledge on the role of MSCs in osteoimmunology, with a focus on how their secretome and EVs integrate immune modulation with bone regeneration. We discuss the mechanisms underlying MSC-mediated regulation of innate and adaptive immune cells, examine emerging cell-free therapeutic strategies based on secretome and EV delivery, and outline the main challenges that must be addressed to advance these approaches towards clinical application.