{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:33:51Z","timestamp":1791192831561,"version":"4.1.0"},"reference-count":168,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education (MOHE), Malaysia","doi-asserted-by":"crossref","award":["FRGS\/1\/2023\/SKK11\/UKM\/03\/1"],"award-info":[{"award-number":["FRGS\/1\/2023\/SKK11\/UKM\/03\/1"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Extracellular vesicle (EV)-based therapies have emerged as promising, cell-free approaches for dental tissue regeneration. This narrative review integrates mechanistic insights, therapeutic efficacy data, and safety and delivery considerations from in vitro and in vivo studies to elucidate the molecular mechanisms by which EVs, particularly those from dental pulp stem cells (DPSCs) and mesenchymal stem cells (MSCs), drive regenerative processes via key signalling axes (PI3K\/Akt, MAPK, BMP\/Smad, and Hedgehog). Preclinical studies demonstrate that unmodified and engineered EVs enhance odontogenic differentiation, angiogenesis, bone repair, and immunomodulation in models of pulp regeneration, alveolar bone defects, osteonecrosis, and periodontitis. Isolation and purification methodologies were also evaluated, comparing ultracentrifugation, size-exclusion chromatography, and density-cushion approaches, and discussing how protocol variations affect EV purity, dosing metrics, and functional reproducibility. Early-phase clinical evaluations report only low-grade transient adverse events, underscoring a generally favourable safety profile. Despite these encouraging results, significant challenges remain: heterogeneity in EV cargo composition, lack of standardised potency assays, and incomplete long-term safety data. The review highlights the urgent need for rigorous, harmonised regulatory frameworks and robust quality control measures to ensure that EV-based modalities can be translated into safe, effective, and reproducible therapies in regenerative dentistry.<\/jats:p>","DOI":"10.3390\/ijms27020798","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T18:40:09Z","timestamp":1768329609000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Safety Assessment of Extracellular Vesicle-Based Therapy in Regenerative Dentistry"],"prefix":"10.3390","volume":"27","author":[{"given":"Bing-Huan","family":"Chuah","sequence":"first","affiliation":[{"name":"Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-5145","authenticated-orcid":false,"given":"Jia-Xian","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3838-9141","authenticated-orcid":false,"given":"Xin-Fang","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2219-6297","authenticated-orcid":false,"given":"Kok-Lun","family":"Pang","sequence":"additional","affiliation":[{"name":"Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Petaling Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Rou","family":"Farm","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6679-9319","authenticated-orcid":false,"given":"Masfueh","family":"Razali","sequence":"additional","affiliation":[{"name":"Department of Restorative Dentistry, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0200-086X","authenticated-orcid":false,"given":"Sook-Luan","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Doyle, L.M., and Wang, M.Z. 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