DNA Supramolecular Hydrogel Alters Exosomal microRNA Atlas and Paracrine Secretory Profile of MSCs to Promote Bone Remodeling and Ameliorate Osteoradionecrosis of the Jaw

Osteoradionecrosis of the jaw (ORNJ) is a severe complication of head and neck radiotherapy, characterized by a hostile tissue microenvironment that hinders healing. To address the limitations of mesenchymal stem cell (MSC) therapy, such as rapid dispersion and clearance, we developed an injectable, shear-thinning 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‑Integrin and Hippo‑YAP mechanotransduction pathways. This directed a shift toward a pro-regenerative exosomal miRNA profile, notably enriching miR‑146a‑5p and reducing miR‑125b‑5p. In a murine ORNJ model, this MSC-laden hydrogel orchestrated a coupled bone-remodeling 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.