Engineered Biomimetic Nanoparticles With Targeted Delivery of Chlorothiazide for the Treatment of Inflammatory Bowel Disease

ABSTRACT While conventional treatment strategies for inflammatory bowel disease (IBD) focus primarily on suppressing overactive immunity, there is still a lack of definitive interventions targeting key pathological mechanisms, such as intestinal barrier dysfunction, dysbiosis of the gut microbiome, and disrupted mucosal immune regulation. Using a high‐throughput drug screening platform, the present study successfully identified chlorothiazide (Chl), a lead compound with anti‐inflammatory potential, from a library of 3152 natural compounds. To further increase the bioavailability of Chl and mitigate its potential toxicity, we constructed a biomimetic delivery system based on engineered bacterial membrane‐encapsulated reactive oxygen species (ROS)‐responsive biomimetic nanoparticles (CHM NPs). This delivery system achieved targeted accumulation in inflamed colonic tissue in a mouse model of acute colitis and effectively facilitated the restoration of epithelial barrier function. Moreover, CHM NPs significantly altered the gut microbiome, increasing overall microbial abundance and diversity while increasing the abundance of gut Lactobacillus , which plays a crucial role in maintaining gut microecological homeostasis. We systematically elucidated the multifaceted mechanisms by which CHM NPs regulate gut homeostasis, remodel the microbial composition, and modulate innate immunity. These findings provide novel theoretical foundations and potential intervention strategies for the treatment of IBD and other related inflammatory conditions.