ROS-responsive nanozyme hydrogel reprograms repair signaling networks in radiation-induced skin injury

Radiation-induced skin injury (RISI) is a common radiotherapy complication, characterized by excessive accumulation of reactive oxygen species (ROS) and disruption of the wound-healing microenvironment. Here, we report a ROS-responsive hydrogel incorporating ultrasmall Cu 5.4 O nanoparticles as ROS-regulating nanozymes, designated Cu 5.4 O@PVA/B/Gel. Embedded in a dynamic polymer network, the hydrogel enables ROS-triggered nanoparticle release and antioxidant activity under oxidative conditions. In vitro, Cu 5.4 O@PVA/B/Gel reduced oxidative stress and attenuated inflammation and apoptosis-related responses while promoting cell migration following irradiation. In a RISI mouse model, the hydrogel promoted wound closure, enhanced angiogenesis and vascular maturation, and improved collagen organization and extracellular matrix remodeling. Proteomic analysis and molecular validation revealed treatment-associated alterations in HIF-1- and NF-κB-related signaling, along with changes in markers of oxidative stress, inflammation, apoptosis, angiogenesis, and fibrosis-related responses. Functional perturbation experiments using HIF-1α knockdown and TNF-α stimulation further supported the involvement of HIF-1 and NF-κB signaling in the therapeutic response. Moreover, Cu 5.4 O@PVA/B/Gel reduced CD86⁺F4/80⁺ macrophages while increasing CD206⁺F4/80⁺ macrophages, indicating a shift toward an M2-like phenotype. These findings demonstrate that Cu 5.4 O@PVA/B/Gel enables ROS-responsive modulation of the irradiated skin microenvironment by coordinating multiple repair-associated processes. More broadly, this work highlights a design strategy for integrating ROS-responsive nanozyme release, catalytic antioxidant activity, and coordinated regulation of tissue repair within a single therapeutic platform for radiation-induced injury. Schematic illustration of the fabrication, ROS-responsive release, and therapeutic mechanisms of the Cu 5.4 O@PVA/B/Gel hydrogel in RISI