Here we show the ROS-responsive nanoparticles carrying the Fc-fused PD-L1 for the targeted treatment of colitis (named PD-L1-Fc/Oxi-αCD nanoparticles) can effectively deliver PD-L1-Fc to the inflamed colon and obviously alleviate the symptoms of acute and chronic colitis by regulating the immune cells/cytokines associated with inflammation, as well as the microbial community and SCFA metabolism in the colon. This evidence concerns the gene CD274 and Chronic colitis.