Stimuli-responsive hydrogels based on cascade reactions: a novel strategy to promote the efficient repair of diabetic wounds

The impaired healing of diabetic wounds is caused by complex multifactorial pathologies and conventional therapeutic approaches often show limited efficacy. In recent years, stimulus-responsive hydrogels based on cascade reactions have become a promising approach in the management of diabetic wounds. These hydrogels are designed to react to particular characteristics of the wound microenvironment, such as glucose concentration, pH, reactive oxygen species (ROS) and enzyme activity, allowing spatiotemporally controlled drug release and synergistic multi-target control. This review focuses on the recent development in understanding of the pathophysiology of diabetic wounds, immune microenvironment modulation, and the development of stimuli-responsive cascade hydrogels, as well as the challenges. By integrating responsive moieties, these hydrogels dynamically control the polarization of immune cells and scavenging of ROS. Furthermore, cascade systems, from single-step to multistep design, enable precise spatiotemporal activation and coordinate antibacterial, antioxidant and pro-regenerative effects. Additionally, emerging technologies such as AI-assisted modeling, biosensing-guided feedback, and organ-on-a-chip platforms have great potential to improve the rational design and predictive validation of cascade hydrogel systems, paving the way for intelligent and personalized diabetic wound therapies.