<p>Radioimmunotherapy has been recognized as a promising strategy for the treatment of colorectal cancer; however, it faces several challenges, including limited efficacy, weak immune activation, and severe radiation-induced colitis. To address these issues, we developed hollow mesoporous silica nanoparticles (^SeH-MONs) that integrate dynamic diselenide bonds, exhibiting high drug loading ability as well as X-ray-responsive degradation and release properties. The degradation products derived from diselenide bonds differentially modulate selenometabolism in colorectal cancer cells and intestinal epithelial cells, leading to increased reactive oxygen species (ROS) generation in tumor cells while mitigating radiation-induced damage in normal cells. After optimizing the content of diselenide bonds, ^SeH-MONs, combined with radiotherapy, not only resulted in enhanced anticancer activity and elicited a sequence of immunogenic cell death but also simultaneously achieved alleviation of radiation-induced intestinal injuries. When loaded with immunomodulators, indoleamine-2,3-dioxygenase inhibitors, ^SeH-MONs enabled the notable suppression of aggressive peritoneal metastatic colon cancer along with low systemic toxicity. This study reveals the therapeutic potential and mechanism of degradable ^SeH-MONs beyond their drug delivery ability, thus providing a promising nanoplatform for the highly efficient radioimmunotherapy- and radiation-induced ablation of colitis.</p> Graphical Abstract <p></p>