Nanohybrid Hydrogels Spatiotemporally Restore Infectious Bone Defects via Mitochondrial Homeostasis-Driven Immunomodulation and Vascular-Bone Coupling Synergy

Regeneration of infected bone defects (IBDs) requires biomaterials capable of dynamically coordinating antimicrobial, anti-inflammatory, and osteogenic functions. Overcoming the spatiotemporal mismatches in treating IBDs remains a critical challenge. Here, we designed a temporally controlled therapy based on gelatin methacrylate (GelMA)-based nanocomposite hydrogels (GCS) coembedded with sulfur quantum dots (SQDs) nanoenzymes and calcium-phosphorus oligomers (CPOs.) The GCS platform enables a three-phase therapy targeting the healing of IBDs: (1) effective inactivation of bacteria is achieved by SQDs weakly interacting with the hydrogel after early and rapid release; (2) the mitochondrial homeostatic balance is maintained through SQDs-mediated reactive oxygen species scavenging that restores ATP synthesis, which in turn inhibits inflammatory cascade-associated protein expression and drives macrophage M2 polarization; and (3) sustained CPO delivery initiates vascular coupling and osteogenic differentiation during tissue regeneration. In a rat model of IBDs, GCS reached a complete bone bridge at week 8 with a 46.6 ± 2.3% new bone volume. This work pioneers nanozyme-driven mitochondrial-immune axis regulation through programmable material dynamics, offering a paradigm for functional hydrogel design in infected tissue regeneration.