Ulcerative colitis (UC) involves a complex interplay of mucosal inflammation, intestinal barrier dysfunction, and gut dysbiosis, all exacerbated by elevated reactive oxygen species (ROS). Existing therapies often fail to concurrently address these interrelated pathologies. Here we present an orally administrable nanocage system that targets both host cells and gut microbiota and can simultaneously address immune dysregulation, epithelial damage, and microbial imbalances for UC treatment when loaded with antioxidant enzymes. This system features a poly(tertiary amine oxide) (PTAO)-based zwitterionic shell and ROS-labile cross-linkers around individual protein molecules. This structure provides robust cargo protection and retention during gastrointestinal transit and enables ROS-triggered release at inflamed sites. Upon internalization by intestinal epithelial cells and macrophages, the nanocages can be directed to mitochondria for efficient ROS scavenging, which promotes epithelial repair and macrophage repolarization. Moreover, the PTAO shell provides bacterial permeability that allows direct enzyme delivery into gut microbes, thus protecting them from oxidative damage and restoring microbial balance. In mouse models of UC and acute radiation colitis, this multifunctional system effectively alleviated inflammation, restored gut homeostasis, and reduced colonic damage, demonstrating its promising therapeutic potential for colitis treatment.