Multifunctional Cerium Single‐Atom Photothermal Hydrogel for Regenerative Microenvironment Remodeling and Diabetic Bone Defect Repair

ABSTRACT

Diabetic bone defects feature persistent oxidative stress, chronic inflammation, impaired angiogenesis, and stem cell dysfunction, creating a regenerative microenvironment poorly addressed by single‐function biomaterials. We develop a pathology‐oriented multifunctional hydrogel integrating cerium single‐atom/polydopamine nanozymes and SDF‐1 within a GelMA matrix with near‐infrared (NIR)‐responsive photothermal functionality. The Ce SAs/PDA nanozyme scavenges multiple reactive oxygen species (ROS), while polydopamine provides photothermal activity and supports controlled release; SDF‐1 promotes bone marrow mesenchymal stem cell (BMSC) recruitment and angiogenesis. Under diabetic stress, the hydrogel reduces ROS accumulation, preserves mitochondrial membrane potential, alleviates DNA damage, and attenuates mesenchymal stem cell senescence, thereby restoring proliferative and osteogenic capacity. It also shifts macrophages toward a reparative phenotype, enhances endothelial migration and vascular network formation, and provides NIR‐triggered antibacterial activity. Transcriptomic and redox‐manipulation analyses further associate these effects with restoration of redox homeostasis and modulation of AGE‐RAGE‐ and PI3K‐AKT‐related signaling. In a diabetic calvarial defect model, the hydrogel enhances bone regeneration and neovascularization while reducing inflammatory and senescence‐associated signals. This study establishes a pathology‐oriented biomaterial strategy coupling single‐atom catalysis, photothermal regulation, and chemokine‐mediated repair to simultaneously address major pathological barriers to diabetic bone regeneration.