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

Xiaoxue Fu1, Zhenyu Luo1, Yuqi Guo2

  • 1Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, People's Republic of China.

Nature Communications
|November 21, 2025
PubMed
Summary

This study presents a novel multifunctional hydrogel for treating diabetes mellitus (DM) bone defects. The hydrogel addresses hyperglycemia, inflammation, and bone remodeling issues, promoting effective bone regeneration in diabetic patients.

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Area of Science:

  • Biomaterials Science
  • Regenerative Medicine
  • Nanotechnology

Background:

  • Diabetes mellitus (DM) impairs bone healing through hyperglycemia, chronic inflammation, and altered bone remodeling.
  • Current therapies for DM-related bone defects lack comprehensive strategies to address these interconnected pathological factors.

Purpose of the Study:

  • To design and develop a glucose/ROS-responsive multifunctional hydrogel (AAT-ZCG) for enhanced bone defect regeneration in a diabetic microenvironment.
  • To concurrently target hyperglycemia, inflammation, and dysregulated bone remodeling in DM bone defects.

Main Methods:

  • Fabrication of a hydrogel integrating tannic acid (TA) and a cascade nanozyme (ZCG: cerium-zoledronic acid-glucose oxidase).
  • In vitro and in vivo evaluation of the hydrogel's stimuli-responsive release, glucose depletion, ROS scavenging, macrophage modulation, angiogenesis, and osteogenesis.
  • Transcriptomic analysis to elucidate the molecular mechanisms underlying bone regeneration.

Main Results:

  • The AAT-ZCG hydrogel demonstrated stimuli-responsive release of TA and ZCG in DM microenvironments.
  • The hydrogel effectively depleted glucose, scavenged ROS, modulated macrophage polarization, and promoted angiogenesis and osteogenesis.
  • Zoledronic acid release inhibited excessive osteoclast activation, and transcriptomic analysis revealed upregulation of the FOXO1 transcription factor.

Conclusions:

  • The multifunctional AAT-ZCG hydrogel provides a consolidated and effective strategy for DM bone defect regeneration by addressing multiple pathological factors.
  • This approach overcomes the limitations of single-target therapies for diabetic bone defects, offering a promising therapeutic platform.