Polygonatum sibiricum polysaccharide-based hydrogels regulate macrophage mitochondrial homeostasis for the treatment of radiodermatitis.

Radiation-induced skin injury (RISI) is the major complication of tumor radiotherapy, and the key to its refractory nature lies in the persistent oxidative stress caused by ionizing radiation. It is noteworthy that this process is closely associated with the disruption of mitochondrial homeostasis in macrophages. Injured mitochondria not only amplify reactive oxygen species (ROS) production but also drive the polarization of macrophages toward a pro-inflammatory phenotype, thereby impeding tissue repair. However, effective strategies to restore macrophage mitochondrial homeostasis for RISI treatment remain limited. This study designed an immunomodulatory dual-network hydrogel (PCA) composed of oxidized polygonatum sibiricum polysaccharide, quaternized chitosan and sodium alginate. The PCA hydrogel exhibited excellent radioprotective effects on keratinocytes against ionizing radiation injury in vitro, promoted wound healing, facilitated macrophage M2 polarization, and suppressed inflammation in a mouse radiodermatitis model. It was further demonstrated that the radioprotective mechanism of PCA hydrogel in macrophages involves scavenging mitochondrial ROS, maintaining the integrity of mitochondrial ultrastructure and membrane potential, restoring oxidative phosphorylation to remodel energy metabolic homeostasis, and ameliorating ionizing radiation-induced structural and functional abnormalities of mitochondria. Notably, PCA inhibited the cytoplasmic leakage of mitochondrial mtDNA, alleviated radiation-mediated excessive inflammation, and promoted the polarization of macrophages toward a reparative phenotype. Collectively, PCA hydrogel protects mitochondrial homeostasis and modulates inflammatory responses, providing a promising candidate strategy for the treatment of radiodermatitis.