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Oral potentially malignant disorders (OPMDs) predispose to certain HNCs. Recent studies suggest emerging roles of extracellular vesicles (EVs) in malignant transformation and provide potential in the management of HNC. This systematic review aimed to evaluate the role of EVs in HNC and OPMDs. The systematic review followed PRISMA\u20102020 guidelines and was registered with PROSPERO. A comprehensive literature search was conducted in five electronic databases (Medline, Scopus, Embase, Cochrane and Web of Science), yielding 3705 initial records. Following de\u2010duplication and independent screening, 237 eligible articles were included. Data extraction was performed by two independent reviewers. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools. Thematic analysis with narrative data synthesis was conducted and the results were organised under the following subthemes: EV isolation and characterisation methods, EV role in cancer and OPMDs progression, immune modulation, biomarker potential, and therapeutic applications. Studies included in the review were published between \u201c1985\u20132025\u201d and showed an accelerated growth in EV research after 2020. Most of the studies relied on traditional isolation and characterisation techniques including ultracentrifugation, transmission electron microscopy and flow cytometry. Most evidence was reported from preclinical studies and demonstrated EVs\u2019 promise as biomarkers for early detection, prognostication, and therapeutic targets. However, the findings also underscored the need for standardised protocols. Current evidence on EVs\u2019 role as drivers of epithelial mesenchymal transition, invasion, immune escape, metabolic reprogramming, and angiogenesis in the pathogenesis of HNC are summarised together with the role of EVs as biomarkers in HNC and potential applications in HNC therapy and therapy resistance. Mechanistic insights into the biological behaviour of EVs in HNC are provided and evidence\u2010based recommendations for future research are proposed in this review.<\/jats:p>","DOI":"10.1002\/jex2.70164","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:01:46Z","timestamp":1784293306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Vesicles in Head and Neck Cancer\u2014A Systematic Review"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7770-5893","authenticated-orcid":false,"given":"Abdallah","family":"Swaid","sequence":"first","affiliation":[{"name":"School of Dentistry University of Birmingham  Birmingham UK"},{"name":"Institute of Dentistry University of Aberdeen  Aberdeen UK"},{"name":"Faculty of Dentistry Ibn Sina University for Medical Sciences  Amman 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