Stimuli-Responsive Hydrogels for Radiation-Induced Skin Injury: From Passive Barriers to Autonomous Drug Delivery Systems

Abstract Radiation-induced skin injury (RISI) affects over 95% of radiotherapy patients. Current clinical management remains confined to passive supportive care, lacking mechanistic precision for RISI's unique pathophysiology. This review adopts a function-centric perspective, classifying hydrogel systems across three generations: first-generation passive moisture barriers; second-generation bioactive platforms incorporating antioxidants, growth factors, stem cells, and exosomes; and third-generation stimuli-responsive systems integrating autonomous drug release, self-healing capabilities, and biosensor monitoring. We establish quantitative design thresholds by correlating RISI microenvironment parameters (pH 6.5-7.0, ROS 100-500 μM, MMP-9 elevation 5-10×) with responsive polymer specifications. Single-cell transcriptomic analysis has identified pro-inflammatory IL-17+ secretory fibroblasts and dysfunctional lymphatic endothelial cells as key dysregulated populations, thereby defining precise cellular targets amenable to hydrogel-based intervention. However, randomized trials demonstrate that certain hydrogel formulations unexpectedly prolonged healing, underscoring the need for design strategies based on quantitative pathophysiological insights rather than passive empiricism. We systematically examine enabling technologies—AI-guided materials optimization, 3D bioprinting, and wearable biosensor integration—while addressing translational barriers including regulatory complexity, manufacturing scalability, and standardized preclinical models. This framework provides actionable design principles to accelerate clinical deployment of next-generation hydrogels for millions of cancer survivors.