Yang Shu, Zhiqiang Luo, Zhi Tang, Wei Li, Fei Sun, Ting Dong, Cheng Zhang, Xiaobin Luo, Zhixiong Luo, Xijuan Liu, Wenxing Liang, Min Zhou, Xiaohui Zhang, Xiangqi Qin, Wenjie Su, Hui Xiong
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.