In Situ-Forming Bioresponsive Liposome-Anchored Hydrogel Restores Redox-Immune Homeostasis in Mucosal Macrophages for Radiation-Induced Rectal Injury Repair

Abstract Radiation-induced rectal injury (RRI) is a prevalent complication of pelvic radiotherapy that severely affects the life quality of patients, but its effective treatment remains a major challenge in the clinic. Herein, we identify that the redox-immune dyshomeostasis of mucosal macrophages as a major pathological driver of RRI-associated acute inflammation and chronic fibrosis and developed an in situ forming reactive oxygen species (ROS)-responsive liposome-anchored hydrogel (Lip@H151@TK-PF127 Gel) for effective RRI repair. For this purpose, liposomes were further grafted with mannose moieties via thioketal (TK) linkers for loading cGAS-STING inhibitor H151, which were further conjugated onto the TK-PF127 Gel. The Lip@H151@TK-PF127 Gel precursors could be facilely administered to the RRI site via enema and undergo temperature transition to achieve in situ gelation, which would be subsequently activated by local ROS to trigger Lip-TK-Man@H151 release. Lip-TK-Man@H151 could be selectively taken up by inflammatory mucosal macrophage and skew them toward the anti-inflammatory and repair-associated macrophage state through restoring redox-immune homeostasis via cooperative TK-enabled ROS scavenging and cGAS-STING inhibition, hallmarked by upregulated IL-10 expression. Owing to these merits, the Lip@H151@TK-PF127 Gel treatment effectively ameliorated the acute epithelial damage post irradiation while abrogating the risk of intestinal fibrosis in vivo. These findings corroborate Lip@H151@TK-PF127 Gel as a promising strategy for RRI treatment in the clinic.