An Immunoregulation Hydrogel with Controlled Hyperthermia‐Augmented Oxygenation and ROS Scavenging for Treating Diabetic Foot Ulcers

AbstractDiabetic foot ulcers (DFUs), a serious and increasingly common chronic issue among diabetics, often do not respond well to generalized treatment strategies. Hypoxia and the overexpression of reactive oxygen species (ROS), resulting in inflammatory dysregulation and subsequent imbalance in macrophage phenotypes, are critical factors contributing to the prolonged non‐healing of DFU wounds. These two issues often interact in a continuous, problematic cycle. Presently, there is a lack of comprehensive strategies aimed at addressing both of these factors simultaneously to interrupt this detrimental cycle. Herein, an immunomodulatory hydrogel (PHG2) is developed for reshaping the hostile DFU microenvironment. The engineered PHG2 not only removes excess internally‐produced ROS but also generates O2, with its efficiency further boosted by local hyperthermia (42.5 °C) activated by near‐infrared light. Through both in vitro and in vivo studies, along with transcriptomic assessment, it is confirmed that PHG2 disrupts the detrimental feedback loop between ROS and inflammation while also lowering the M1/M2 macrophage ratio. Such discoveries contribute to a significant enhancement in the healing process of injuries that undergo a gradual increase in movement, covering wounds from the back, mouth, to the foot. Ultimately, this method provides an easy, safe, and highly effective solution for treating DFUs.