Ascidian‐Inspired Temperature‐Switchable Hydrogels with Antioxidant Fullerenols for Protecting Radiation‐Induced Oral Mucositis and Maintaining the Homeostasis of Oral Microbiota

Abstract A key characteristic of radiation‐induced oral mucositis (RIOM) is oxidative stress mediated by the “reactive oxygen species (ROS) storm” generated from water radiolysis, resulting in severe pathological lesions, accompanied by a disturbance of oral microbiota. Therefore, a sprayable in situ hydrogel loaded with “free radical sponge” fullerenols (FOH) is developed as antioxidant agent for RIOM radioprotection. Inspired by marine organisms, 3,4,5‐trihydroxyphenylalanine (TOPA) which is enriched in ascidians is grafted to clinically approved temperature‐switchable Pluronic F127 to produce gallic acid (containing the TOPA fragment)‐modified Pluronic F127 (MGA) hydrogels to resist the fast loss of FOH via biomimetic adhesion during oral movement and saliva erosion. Based on this, progressive RIOM found in mice is alleviated by treatment of FOH‐loaded MGA hydrogels whether pre‐irradiation prophylactic administration or post‐irradiation therapeutic administration, which contributes to maintaining the homeostasis of oral microbiota. Mechanistically, FOH inhibits cell apoptosis by scavenging radiation‐induced excess ROS and up‐regulates the inherent enzymatic antioxidants, thereby protecting the proliferation and migration of mucosal epithelial cells. In conclusion, this work not only provides proof‐of‐principle evidence for the oral radioprotection of FOH by blocking the “ROS storm”, but also provides an effective and easy‐to‐use hydrogel system for mucosal in situ administration.