Abstract
Diabetic bone defects are associated with chronic inflammation, impaired healing, and high susceptibility to infection, posing serious clinical challenges. Recent studies have identified macrophage metabolic dysfunction as a key contributor to this impaired regenerative process. Targeting macrophage metabolism offers a promising strategy to rebalance the inflammatory microenvironment and promote bone repair. Metformin, a well-established antidiabetic agent, has been shown to reprogram macrophage metabolism by enhancing oxidative phosphorylation and promoting anti-inflammatory M2 polarization. However, its therapeutic efficacy is limited by poor local retention and lack of antibacterial activity. To overcome these limitations, we developed a multifunctional self-assembled hydrogel (M - C Gel@Met) based on multivalent PEG-antimicrobial polymers and clay nanosheets, enabling sustained co-delivery of metformin and antimicrobial peptides. This hydrogel not only mimics the dynamic structure of the extracellular matrix and adapts to irregular defects, but also provides potent antibacterial protection while reprogramming macrophage metabolism. In diabetic bone defect models, M - C Gel@Met effectively alleviated inflammation, enhanced osteogenesis, and accelerated bone regeneration. Overall, this strategy presents a biomaterial-based immunometabolic strategy integrating infection control and metabolic modulation for diabetic bone repair.