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As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti\u2010inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage\u2010derived exosomes (M2\u2010exos) can actively target inflammatory sites and modulate immune microenvironments, M2\u2010exos can effectively treat periodontitis. Excessive endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) are highly destructive pathological characteristics during inflammatory periodontal bone loss. Although melatonin has antioxidant and anti\u2010inflammatory effects, studies focusing on melatonin ER stress modulation remain limited. This study fabricates engineered M2\u2010exos loading with melatonin (Mel@M2\u2010exos) for treating periodontitis. As a result, M2\u2010exos drive an appropriate and timely macrophage reprogramming from M1 to M2 type, which resolves chronic inflammation and accelerated periodontal healing. Melatonin released from Mel@M2\u2010exos rescues the osteogenic and cementogenic differentiation capacity in inflammatory human periodontal ligament cells (hPDLCs) by reducing excessive ER stress and UPR. Injectable gelatin methacryloyl (GelMA) hydrogels with sustained\u2010release Mel@M2\u2010exos accelerate periodontal bone regeneration in rats with ligation\u2010induced periodontitis. Taken together, melatonin engineering M2 macrophage\u2010derived exosomes are promising candidates for inflammatory periodontal tissue regeneration.<\/jats:p>","DOI":"10.1002\/advs.202302029","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T23:14:37Z","timestamp":1689376477000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":167,"title":["Melatonin Engineering M2 Macrophage\u2010Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy"],"prefix":"10.1002","volume":"10","author":[{"given":"Ya","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Oral and Cranio\u2010Maxillofacial Surgery Shanghai Ninth People's Hospital, College of Stomatology Shanghai Jiao Tong University School of Medicine National Clinical Research Center for Oral Diseases Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of 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