{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T20:42:22Z","timestamp":1793220142498,"version":"4.5.0"},"reference-count":200,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>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)\u2013derived 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\u2014including microRNAs (miRNAs), proteins, and lipids\u2014promote sprouting, vessel stabilization, and angiogenesis\u2013osteogenesis 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.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1784567","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:59:01Z","timestamp":1775800741000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Stem cell-derived extracellular vesicles -mediated bone regeneration: mechanisms, targeted delivery, and clinical perspectives in promoting angiogenesis"],"prefix":"10.3389","volume":"14","author":[{"given":"Yang","family":"Shu","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Hunan University of Chinese Medicine","place":["Changsha, Hunan, China"]},{"name":"Department of Graduate School, Hunan University of Chinese Medicine","place":["Changsha, Hunan, 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