Glucose/ROS/pH Triple Editing “Domino Hydrogel” Accelerates Diabetic Wound Healing via Hypoglycemic, Antioxidant, Antibacterial, and Macrophage Polarization

Diabetic foot ulcers are a severe complication of diabetes, imposing a substantial burden on both health and the economy. Bacterial infections, high glucose levels, and the intricate microenvironment of oxidation collectively hinder the healing of diabetic wounds. Hydrogels responsive to the microenvironment have demonstrated significant advantages in treating diabetic wounds due to their ability to release drugs on demand. The study utilized modified pectin and hyaluronic acid to develop a self-recognizing and self-treating composite hydrogel. Within this hydrogel, insulin was encapsulated using a metal–organic framework with an ROS-responsive coating (ZIF-8@PEG-TK). Under high glucose and low pH conditions, INS@ZIF-8@PEG-TK was released and responded to excess ROS, ensuring sustained insulin release. This hydrogel exhibited excellent antimicrobial and antioxidant activities along with biocompatibility. It promoted the polarization of macrophages, reduced glucose levels, and accelerated cell proliferation and collagen deposition, leading to rapid wound closure. Accordingly, the microenvironment-responsive hydrogel is a promising biomaterial for treating chronic diabetic wounds.