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To address the limitations of mesenchymal stem cell (MSC) therapy, such as rapid dispersion and clearance, we developed an injectable, shear\u2010thinning DNA supramolecular hydrogel (DNASH) as a 3D scaffold. The DNASH matrix significantly prolonged the local retention of MSCs and their exosomes for over 3 weeks. Crucially, the scaffold actively reprogrammed the MSC secretome by modulating the FAK\u2011Integrin and Hippo\u2011YAP mechanotransduction pathways. This directed a shift toward a pro\u2010regenerative exosomal miRNA profile, notably enriching miR\u2011146a\u20115p and reducing miR\u2011125b\u20115p. In a murine ORNJ model, this MSC\u2010laden hydrogel orchestrated a coupled bone\u2010remodeling process, effectively clearing necrotic bone while stimulating robust osteogenesis. The treatment restored mandibular architecture, reduced systemic inflammation, and improved tissue homeostasis, presenting a clinically promising strategy for ORNJ repair.<\/jats:p>","DOI":"10.1002\/adma.202523658","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:48Z","timestamp":1771564908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA Supramolecular Hydrogel Alters Exosomal microRNA Atlas and Paracrine Secretory Profile of MSCs to Promote Bone Remodeling and Ameliorate Osteoradionecrosis of the Jaw"],"prefix":"10.1002","volume":"38","author":[{"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Prosthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology NMPA Key Laboratory For Dental Materials  Beijing P. 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