Tofacitinib Citrate Coordination‐Based Dual‐Responsive/Scavenge Nanoplatform Toward Regulate Colonic Inflammatory Microenvironment for Relieving Colitis

Abstract Ulcerative colitis is an inflammation of the colon characterized by immune dysregulation and intestinal inflammation. Developing safe oral nanomedicines that suppress intestinal inflammation, while modulating colonic inflammatory microenvironment by scavenging reactive oxygen species (ROS) and hydrogen sulfide (H 2 S) is crucial for the effective treatment of colitis. Here, the tofacitinib citrate and copper coordination‐based nanoparticle (TF‐Cu nanoparticle, T‐C) to dual‐scavenge ROS and H 2 S by coordination competition is synthesized. Moreover, the coordination of T‐C using computer simulation is explored. To enhance the acid stability and inflammatory targeting of T‐C, it is encapsulated with hyaluronic acid‐modified chitosan, along with a calcium pectinate coating (T‐C@HP). Owing to the dual pH/pectinase‐responsive characteristics of T‐C@HP, the nanoplatform can target inflamed colonic lesions, inhibiting phosphorylated Janus kinase 1. Furthermore, T‐C@HP scavenges ROS and H 2 S, as well as increases NADPH levels, which is investigated by combining biosensor (HyPer7 and iNap1/c) and chemical probes. T‐C@HP also alleviates colitis by regulating the colonic inflammatory microenvironment through multiple processes, including the modulation of apoptosis, macrophage polarization, tight junction, mucus layer, and intestinal flora. Complemented by satisfactory anti‐inflammatory and biosafety results, this nanoplatform represents a promising, effective, and safe treatment option for colitis patients.