A Self‐Adaptive Programming Strategy Enables Local Microenvironment Modulation and Temporal Immunomodulation for Diabetic Infected Bone Regeneration

The repair of diabetic bone defects remains challenging due to disrupted bone immune homeostasis and increased susceptibility to infection. Under hyperglycemic conditions, the immune microenvironment fails to switch between the pro‐inflammatory environment required for pathogen clearance and the anti‐inflammatory environment for osteogenesis. Here, a glucose‐responsive hydrogel (PEG‐ZnO‐sita) is developed by integrating zinc oxide (ZnO) and sitagliptin into a network formed by dopamine‐modified tetra‐armed poly(ethylene glycol) succinimidyl glutarate (DA‐PEG‐SG) and phenylboronic acid‐modified gelatin (PBA‐Gel). PEG‐ZnO‐sita, enabled by amidation, phenylboronic ester bonds, and metal‐catechol coordination, confers rapid gelation, injectability, mechanical stability, self‐healing, and robust tissue adhesion, adapting to the local complexity at the bone defect. In a diabetic microenvironment, the rapid breakage of boronate ester bonds triggers the early burst release of Zn 2+ to inhibit infection by promoting M1 polarization, along with sitagliptin‐intervening glucose regulation. Whereafter, the sustained Zn 2+ and sitagliptin release induce M2 polarization and facilitate osteogenic differentiation, demonstrating a self‐adaptive strategy in response to inflammatory environments. Both in vitro and in vivo studies confirm that PEG‐ZnO‐sita effectively promotes bone regeneration by local hyperglycemic microenvironment modulation and sequential regulation of macrophage polarization. So, this temporal immunoregulation of hyperglycemia‐immune‐osteogenic cascade presents a promising strategy for diabetic infected bone defects.