ABSTRACT 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.
Li et al. (2026) studied this question.