{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:16:34Z","timestamp":1787501794516,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background\/Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive condition characterized by bone necrosis, impaired vascularization, and immune dysregulation, often resulting in femoral head collapse. Effective strategies to halt disease progression are limited. Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication and influence osteogenesis, angiogenesis, and immune responses. This review summarizes current evidence on EVs in ONFH and their translational potential. Methods: A structured narrative review of PubMed, Scopus, Web of Science, and Cochrane Central databases was conducted, including in vitro, preclinical, and clinical studies on EVs in ONFH. Data on EV sources, molecular cargo, signaling pathways, functional effects, and translational implications were qualitatively synthesized. No pooled statistical analysis was performed because the extracted data were heterogeneous. Bioinformatic analyses such as Gene Ontology, KEGG enrichment, and protein\u2013protein interaction networks were also summarized. Results: In vitro, EVs from bone marrow mesenchymal stem cells, endothelial cells, and M2 macrophages modulate osteogenic differentiation, angiogenesis, and inflammation. Preclinical studies demonstrate that EV administration reduces femoral head necrosis, improves trabecular structure, and enhances neovascularization. Clinical studies have identified EV-associated molecules (SAA1, C4A, RPS8) linked to disease stage and the risk of femoral head collapse. Bioinformatic analyses connect EV cargo to pathways regulating bone formation, vascularization, immunity, and metabolism. Conclusions: EVs appear to play key roles in ONFH pathogenesis and may represent promising candidates for diagnostic and therapeutic applications. However, current clinical evidence remains limited and requires validation in larger studies. Nonetheless, heterogeneity and limited clinical data require standardized, longitudinal studies to validate their translational relevance.<\/jats:p>","DOI":"10.3390\/jpm16040208","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:25:12Z","timestamp":1775633112000},"page":"208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extracellular Vesicles in Osteonecrosis of the Femoral Head: An Integrated Review of Experimental and Bioinformatic Evidence"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-3623","authenticated-orcid":false,"given":"Elvira Immacolata","family":"Parrotta","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences, \u201cMagna Gr\u00e6cia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8585-2144","authenticated-orcid":false,"given":"Giorgia Lucia","family":"Benedetto","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, \u201cMagna Gr\u00e6cia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-1866","authenticated-orcid":false,"given":"Giovanni","family":"Cuda","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, \u201cMagna Gr\u00e6cia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4063-9821","authenticated-orcid":false,"given":"Umile Giuseppe","family":"Longo","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Roma, Italy"},{"name":"Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Carnevale","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olimpio","family":"Galasso","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8256-7697","authenticated-orcid":false,"given":"Giorgio","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic and Trauma Surgery, \u201cMagna Gr\u00e6cia\u201d University, \u201cRenato Dulbecco\u201d University Hospital, 88100 Catanzaro, Italy"},{"name":"Research Center on Musculoskeletal Health, MusculoSkeletalHealth@UMG, \u201cMagna Gr\u00e6cia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-5612","authenticated-orcid":false,"given":"Michele","family":"Mercurio","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic and Trauma Surgery, \u201cMagna Gr\u00e6cia\u201d University, \u201cRenato Dulbecco\u201d University Hospital, 88100 Catanzaro, Italy"},{"name":"Research Center on Musculoskeletal Health, MusculoSkeletalHealth@UMG, \u201cMagna Gr\u00e6cia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ejrad.2007.03.019","article-title":"Osteonecrosis of the Femoral Head: Etiology, Imaging and Treatment","volume":"63","author":"Malizos","year":"2007","journal-title":"Eur. 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