Carboxymethyl chitosan crosslinked self-assembled collagen hydrogel protects against radiation-induced skin injury by modulating iron homeostasis.

Radiation-induced skin injury (RSI) is a critical complication of radiotherapy, affecting over 95% of patients and causing severe morbidity with treatment interruptions. Clinical therapies fail to address its multifactorial pathogenesis, including vascular dysfunction, oxidative stress, and chronic inflammation. Current clinical chitosan-based wound care materials face challenges like rapid degradation and insufficient mechanical stability. To tackle these, we developed a self-assembled carboxymethyl chitosan-crosslinked collagen hydrogel (Col+CMC) using traceable type I collagen from shad fish scales. This hydrogel forms a stable, porous hydrogel at physiological conditions without external crosslinkers, integrating collagen's structural support with carboxymethyl chitosan's iron-chelating properties. In a murine RSI model, Col+CMC accelerated ulcer repair by promoting collagen remodeling and endothelial angiogenesis, while suppressing oxidative stress and ferroptosis through activation of the GPX4-SLC7A11 pathway. In vitro studies confirmed its robust free radical scavenging capacity and pro-angiogenic effects on endothelial cells. The injectable, self-setting design offers clinical advantages: no crosslinking agents simplify application, traceable aquaculture-derived collagen ensures regulatory compliance, and the composite architecture enables multi-targeted therapy against RSI's pathological drivers. This work presents a biomaterial platform that merges self-assembly functionality with mechanistic targeting of iron homeostasis, addressing critical gaps in RSI management and showcasing translational potential for radiation therapy complications.