Oral of PtCuS nanoclusters mitigates acute radiation-induced intestinal injury by coordinating glutathione metabolism, macrophage repolarization, and gut microbiota.

Acute radiation-induced intestinal injury (ARIII) is a common side effect of abdominopelvic radiotherapy, with severe diarrhea and hematochezia occurring in approximately 60-80% of patients. Radiation inevitably damages the adjacent intestine, generating substantial reactive oxygen species (ROS) that impair intestinal function. Nanozymes, which combine enzyme-like catalytic activities with the advantages of nanomaterials, have broad applications in biomedicine. Applying nanozymes to mitigate radiation-induced intestinal damage represents a promising therapeutic strategy. Here, we developed PtCuS nanoclusters (NCs) with favorable biocompatibility and demonstrated their efficacy in mitigating ARIII after irradiation. PtCuS NCs scavenge ROS via enzyme-mimetic activity and activate glutathione metabolism to mitigate radiation-induced cell death and inflammation. PtCuS NCs also modulate macrophage polarization, suppressing M1-like pro-inflammatory activation and promoting an M2-like reparative phenotype through both direct macrophage regulation and epithelial-protective effects. Furthermore, PtCuS NCs help restore gut microbiota composition and metabolic profiles after irradiation, providing a microbiota-associated component of intestinal protection. Importantly, PtCuS NCs alleviate ARIII without compromising the therapeutic efficacy of radiotherapy. These findings demonstrate that oral administration of PtCuS NCs may safely and effectively mitigate ARIII, highlighting their potential to improve the quality of life of patients undergoing abdominopelvic radiotherapy.