Stem cell-derived extracellular vesicles -mediated bone regeneration: mechanisms, targeted delivery, and clinical...

Angiogenesis is indispensable for bone regeneration and tightly coupled to osteogenesis, yet inadequate vascularization remains a common cause of repair failure in critical-sized defects, compromised fractures, and osteochondral lesions. Conventional growth-factor delivery and cell transplantation rarely reproduce the spatiotemporal vascular program required for functional healing, motivating the search for controllable and translatable alternatives. Mesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EVs) have emerged as a modular, cell-free modality that packages regenerative cues into lipid-bilayer nanoparticles capable of coordinating endothelial activation, immune reprogramming, and osteogenic differentiation. In this review, we (i) delineate phase-resolved angiogenic events across inflammation, callus formation, mineralization, and remodeling; (ii) synthesize mechanistic evidence showing how EV cargos-including microRNAs (miRNAs), proteins, and lipids-promote sprouting, vessel stabilization, and angiogenesis-osteogenesis coupling across models of fractures, segmental/critical-sized defects, osteonecrosis, and alveolar/osteochondral repair; and (iii) critically appraise engineering and delivery strategies (preconditioning, cargo loading, surface functionalization, and biomaterial depots) that enhance lesion exposure, local retention, and sustained bioactivity. To bridge proof-of-concept and a regulatory-ready therapeutic product, we further summarize manufacturing scale-up, quality control beyond minimal EV identity markers, mechanism-anchored potency assays, dosing metrics, biodistribution, and long-term safety considerations, and we highlight the nascent but evolving clinical landscape in bone and joint disorders. Collectively, this review provides a practical roadmap for developing reproducible EV therapeutics that enable vascularized bone regeneration.