Inflammatory bowel disease (IBD) causes damage to patients, and therapy remains a crucial challenge owing to the presence of excessive reactive oxygen species (ROS) and hydrogen sulfide (H(2)S) in colonic inflammatory circulation. Herein, we report a shikonin (SK) and zinc (Zn) driven coordination nanozyme (SK-Zn, S-Z), which effectively scavenged ROS and H(2)S. Furthermore, a pH responsive targeted polymer nanoplatform (S-Z@ChF), consisting of S-Z, chitosan, hyaluronic acid and poly ferulic acid, was developed for the oral treatment of colitis. In vivo experiments revealed that the nanoplatform could target colonic inflammatory lesions, relieve inflammatory index and restore the colonic mechanical barrier. The transcriptomics and pharmacodynamic mechanism analysis revealed that S-Z@ChF scavenged ROS, inhibited nuclear factor kappa-B (NF-kappaB) and pyruvate kinase isozyme type M2 (PKM2) and signal transducer and activator of transcription 3 (STAT3) pathways, balancing the level of macrophage polarization and pro-inflammatory enzyme. Additionally, S-Z@ChF reliably regulated the gut microbiota during H(2)S scavenging. In conclusion, S-Z@ChF, which provides multiple anti-inflammatory pathways and microenvironment reprogramming support for blocking inflammatory circulation, was found to be biologically safe, with significant potential for clinical application in IBD.