Drug-loaded micelles for oral administration are desired for its convenience, low cost and flexibility, but current designs rely on introducing pH responsiveness, leaving problems like drug leakage and low accuracy of targeted delivery un-solved. Herein, we reported an acid-resistant ROS-responsive hyperbranched polythioether which can self-assemble into micellar structure and pass through the gastrointestinal tract without leaking drugs. At the inflammatory lesions, the thioester bonds are oxidized to sulphone groups to significantly increase the hydrophilicity in response to accumulated ROS species and efficiently release the encapsulated drugs. Animal experiments, including the evaluation of bodyweight, colon length, MPO activity, spleen index, histology and quantitative reverse transcription PCR, evidenced that the drug-loaded micelles have improved therapeutic efficiency compared to bare drug administration for the treatment of DSS-induced colitis in mice. This study provides an example of oral administrated micellar system can be extended for the treatment of other intestinal tract diseases.