Microenvironment-responsive multifunctional enzyme-linked hydrogel for diabetic bone defect regeneration

Diabetes mellitus (DM) bone defects face impaired healing due to hyperglycemia, chronic inflammation, and dysregulated bone remodeling, yet existing therapies lack comprehensive strategies targeting these interconnected issues. Herein, a glucose/ROS-responsive multifunctional hydrogel (AAT-ZCG) is designed, integrating tannic acid (TA)-mediated dynamic borate ester bonds and a cascade nanozyme comprising cerium-zoledronic acid-glucose oxidase (ZCG). The hydrogel enables stimuli-responsive release of TA and ZCG within DM microenvironments, depleting glucose via glucose oxidase-mediated catalysis and mitigating inflammation through cerium-mediated ROS scavenging. Moreover, ZCG modulates macrophage polarization, stimulates angiogenesis and enhances osteogenesis. Acidic byproducts trigger ZCG degradation, releasing zoledronic acid to inhibit excessive osteoclast activation. Transcriptomic analysis reveals upregulated forkhead box O1 transcription factor, a key regulator of bone metabolism and inflammation. This platform concurrently addresses pivotal mediators in DM bone defects, overcoming limitations of single-target approaches. By consolidating multifunctional responses, AAT-ZCG provides a concise yet effective strategy for DM bone defect regeneration.