A ROS-responsive nanocarrier co-delivering cerium nanozymes and thalidomide for synergistic ulcerative colitis therapy

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disorder of the gastrointestinal tract, posing major clinical challenges due to its increasing incidence and complex pathogenesis involving immune dysregulation and oxidative stress. Current therapies are often limited by poor efficacy and severe side effects, leaving an urgent need for improved treatments. Here, we present a novel ROS-responsive nanocarrier (TPN) for the synergistic therapy of colitis via ROS scavenging and immune modulation. TPN were fabricated by encapsulating cerium oxide nanozymes (Ceria NPs) and thalidomide (Tha) within a specially designed amphiphilic ROS-responsive polymer (PP). TPN exhibited strong ROS-scavenging activity and ROS-triggered Tha release. <i>In vitro</i>, TPN effectively attenuated ROS-induced oxidative stress and apoptosis. In a DSS-induced mouse colitis model, TPN passively accumulated in the colon and significantly alleviated body weight loss, colon shortening, disease activity index, and histological damage. Mechanistically, TPN modulated the immune response, reduced oxidative stress, and reshaped the gut microbiota toward a healthier composition. Moreover, biosafety assessments confirmed the absence of systemic toxicity. Collectively, these findings demonstrate that TPN represents a potent and safe therapeutic strategy for UC by integrating targeted delivery with synergistic antioxidant and immunomodulatory functions.