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

Xiaoxue Fu, Zhenyu Luo, Yuqi Guo, Weikun Meng, Shue Jin, Junyu Chen, Yongrui Cai, Zeyu Luo, Chao Huang, Anjing Chen, Siqin Guo, Maojia Chen, Zongke Zhou () and Weinan Zeng ()
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Xiaoxue Fu: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Zhenyu Luo: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Yuqi Guo: The 945th Hospital of Joint Logistics Support force of Chinese People ‘ s Liberation Army, Department of Pharmaceutical Sciences
Weikun Meng: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Shue Jin: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Junyu Chen: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Yongrui Cai: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Zeyu Luo: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Chao Huang: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Anjing Chen: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Siqin Guo: Sichuan University, Clinical Research Management Department, West China Hospital
Maojia Chen: Sichuan University, Animal Experimental Center, West China Hospital
Zongke Zhou: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital
Weinan Zeng: Sichuan University, Department of Orthopedics, Orthopedic Research Institute, West China Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65165-5

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