Mn/Zn Bimetallic MOF-Integrated Hydrogel Alleviates Excessive Mitochondrial Fission in BMSCs to Promote Osteoporotic Jawbone Repair.

Osteoporotic jawbone defects show impaired bone healing and insufficient new bone regeneration due to a pathological osteoporotic microenvironment, where chronic inflammation and excessive reactive oxygen species (ROS) accumulation impair the function of bone marrow-derived mesenchymal stem cells (BMSCs). In this study, we find that osteoporotic BMSCs display reduced osteogenic differentiation and migration, accompanied by elevated intracellular ROS levels, mitochondrial dysregulation at both functional and structural levels. Targeting this pathophysiology, we engineer a locally injectable Mn-ZIF-8@GelMA hydrogel by incorporating manganese-doped zeolitic imidazolate framework-8 nanoparticles into a gelatin methacryloyl matrix, synergistically integrating redox regulation with osteogenic stimulation. Mn-ZIF-8@GelMA effectively alleviates oxidative stress, improves mitochondrial function, and the osteogenic competence of osteoporotic BMSCs. Mechanistically, Mn-ZIF-8@GelMA treatment increases mitochondrial antiviral signaling protein (MAVS) expression, reduces dynamin-related protein 1 (DRP1) phosphorylation, and alleviates excessive mitochondrial fission. Mitochondrial disruption and MAVS knockdown further suggest that MAVS and DRP1 may contribute to the mitochondrial remodeling and osteogenic effects of Mn-ZIF-8@GelMA. In vivo, Mn-ZIF-8@GelMA significantly promotes extraction socket repair in osteoporotic mice. This work presents a Mn/Zn bimetallic metal-organic framework (MOF)-integrated GelMA hydrogel for osteoporotic jawbone repair, and highlights redox-mediated mitochondrial regulation of endogenous BMSCs as a promising strategy to overcome impaired bone regeneration under osteoporotic conditions.