Thermosensitive Multifunctional Hydrogel for Boosting Drug-Resistant Infected Diabetic Wound Healing by Integrating Gas Therapy and Cascaded CDT.

The treatment of diabetic wounds remains unsatisfactory due to bacterial infection risks and impaired angiogenesis during the healing. Herein, a multifunctional hydrogel was constructed for boosting multidrug-resistant bacteria-infected diabetic wound healing by integrating gas therapy and cascaded chemical dynamic therapy (CDT). The hydrogel was based on Pluronic F127 and hyaluronic acid (HA), which was loaded with an iron-based metal organic framework (MIL-100(Fe)) coupled with S-nitrosoglutathione (GSNO) and glucose oxidase (GOX) (MIL-100(Fe)@GOX@GSNO@F127-HA, shortly named as MGG@FH). In the hyperglycemic diabetic microenvironment, GOX is activated to reduce local glucose levels and pH while generating hydrogen peroxide (H2O2). MIL-100(Fe) with peroxidase-like activity catalyzes H2O2 to produce reactive oxygen species (ROS), exerting antibacterial effects. GSNO spontaneously releases nitric oxide (NO) to modulate inflammation and promote angiogenesis. The MGG@FH hydrogel downregulates pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) while upregulating the anti-inflammatory factor IL-10. It also enhances angiogenesis and collagen deposition in vivo, significantly accelerating the healing of infected diabetic wounds. Meanwhile, the temperature-sensitive sol-gel transition property of the hydrogel makes it possible for in situ forming gels on the wound site, allowing it to conform to irregular shapes and well fit the depth of the wound. The strategy combines "endogenous improvement" (reducing glucose and pH) with "exogenous resistance" (antibacterial/anti-inflammatory effects), offering an effective approach for comprehensive infected diabetic wound management.