Comprehensive Management of Ulcerative Colitis and its Associated Intra‐Extra Intestinal Complications with a Multifunctional Inulin Hydrogel Complex

Abstract Excessive accumulation of reactive oxygen species (ROS) and dysbiosis of gut microbiota are pivotal etiological factors in the pathogenesis of ulcerative colitis (UC) and its associated intestinal and extraintestinal manifestations (e.g., intestinal microthrombosis, anxiety, and depression symptoms). This investigation presents a multifunctional inulin complex (PB/NKase@Inulin gel) incorporating Prussian blue nanozymes (PB NZs) and the thrombolytic agent nattokinase (NKase) for the therapeutic management of dextran sulfate sodium (DSS)‐induced UC and its associated intestinal and extraintestinal complications. Following oral administration, the PB/NKase@Inulin gel, characterized by prolonged retention of PB NZs and NKase at inflamed colonic sites, can facilitate continuously ROS scavenging, attenuate oxidative stress damage, effectively reduce pro‐inflammatory cytokine levels. Importantly, PB/NKase@Inulin gel can not only robustly inhibit inflammatory microthrombosis formation but also effectively lyses thrombi due to the potent thrombolytic properties of NKase both in vitro and in vivo. Furthermore, the PB/NKase@Inulin gel is able to modulate gut microbiota homeostasis and alleviate multiple stresses responses (including anxiety and depression) in a UC mouse model via microbiota‐gut‐brain (MGB) axis interactions. Overall, the PB/NKase@Inulin gel offers an innovative paradigm for comprehensive therapeutic interventions in DSS‐induced UC and its multifaceted complications.