Triple-responsive supramolecular hydrogel with synergistic photothermal effect regulates inflammatory signaling to remodel the diabetic wound microenvironment and promote chronic wound healing

As one of the representative intractable chronic complications of diabetes, the global incidence of diabetic non-healing wounds has continued to rise as the diabetic population expands. It not only places 15%–25% of patients at amputation risk but also markedly increases the incidence of life-threatening complications such as infection and sepsis, imposing a heavy burden on patients' quality of life and public health systems. Natural polysaccharide derivatives including oxidized hyaluronic acid and hydroxypropyl chitosan served as raw materials, and these materials were respectively subjected to functional modification via grafting of sepia melanin and phenylboronic acid. Via dynamic covalent interactions (borate ester bonds and Schiff bases) together with hydrogen bonding, a supramolecular hydrogel with multi-responsive characteristics to glucose level, pH and ROS level was constructed. Using a diabetic rat model of infected wounds, in-depth investigations were conducted into the wound repair efficacy and underlying mechanisms. Results demonstrated that the hydrogel markedly suppressed the activation of NOD-like receptor and Toll-like receptor signaling pathways, modulated macrophage polarization from the M1 to M2 phenotype, and reversed adverse pathological factors such as hyperglycemia-induced damage, oxidative stress and chronic inflammation via multi-targeted synergistic regulation, thereby effectively promoting wound healing. Focusing on remodeling the pathological microenvironment of diabetic wounds as the core premise, this study developed a specialized dressing for diabetic wounds capable of reversing the adverse microenvironment. It offers a targeted novel strategy for microenvironment modulation to overcome diabetic wound healing barriers, with scientific innovation for addressing clinical challenges and promising translational potential.