Reactive Oxygen Species Scavenging and Thermosensitive Smart Release-Stiffening Integrated Hydrogel for Diabetic Wound Therapy.

Abstract

Diabetic wounds remain a formidable clinical challenge due to excessive reactive oxygen species (ROS) accumulation, impaired immune regulation, and compromised tissue regeneration. Herein, we report a multifunctional thermosensitive smart hydrogel integrating hollow mesoporous MnO₂ nanozymes and transforming growth factor-β1 (TGF-β1) into an adhesive thermosensitive hydrogel (TGF-β1@MATH) for synergistic diabetic wound therapy. The MnO₂ nanozymes efficiently scavenge ROS in the diabetic wound microenvironment, suppressing the Nrf2-HO-1-NQO-1 pathway to alleviate oxidative stress and restore the cell migration capacity. Triggered by body temperature, TGF-β1@MATH undergoes stiffness enhancement and controlled TGF-β1 release: the increased stiffness upregulates integrin β2 (ITGB2) expression in T cells, while TGF-β1 synergizes with ITGB2 to activate the Smad2/3 pathway, promoting regulatory T cell (Tregs) aggregation and secretion of growth factors. <i>In vitro</i> studies confirm that TGF-β1@MATH accelerates fibroblast migration, induces myofibroblast differentiation, and modulates the immune microenvironment. In diabetic mice, TGF-β1@MATH achieves a 95% wound healing rate within 14 days, significantly enhancing re-epithelialization, collagen deposition, angiogenesis, and Tregs recruitment. This integrated design addresses multiple pathological barriers of diabetic wound areas (WA) through ROS scavenging, thermosensitive regulation and immune-modulated regeneration, offering a promising translational strategy for clinical diabetic wound management.