Multifaceted Catalytic Glucose Depletion and Reactive Oxygen Species-Scavenging Nanoenzyme Composite Hydrogel for Facilitating Diabetic Bone Regeneration

Regeneration of diabetic bone defects remains a formidable challenge due to the chronic hyperglycemic state, which triggers the accumulation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To address this issue, we have engineered a bimetallic metal–organic framework-derived Mn@Co₃O₄@Pt nanoenzyme loaded with alendronate and Mg²⁺ ions (termed MCPtA) to regulate the hyperglycemic microenvironment and recover the osteogenesis/osteoclast homeostasis. Notably, the Mn atom substitution in the Co₃O₄ nanocrystalline structure could modulate the electronic structure and significantly improve the SOD/CAT catalytic activity for ROS scavenging. By integration with GOx-like Pt nanoparticles, the MCPtA achieved effective multiple cascade catalytic performance that facilitated the clearance of glucose and ROS. Furthermore, the MCPtA was encapsulated within a glucose-responsive hydrogel cross-linked via a borate ester bond, termed PAM, to evaluate the potential of the composite hydrogel for cranial defect repair in diabetic rats. The in vitro/vivo experiments as well as the RNA sequencing analysis demonstrated that the nanoenzyme composite hydrogel could disrupt the glucose-ROS-induced inflammation and promoted osteogenesis and angiogenesis, in consequence, improving the therapeutic effects for diabetic bone regeneration. This study provided crucial insights into nanoenzyme-mediated microenvironmental regulation for diabetic bone regeneration.