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Using a high\u2010throughput drug screening platform, the present study successfully identified chlorothiazide (Chl), a lead compound with anti\u2010inflammatory 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\u2010encapsulated reactive oxygen species (ROS)\u2010responsive 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\n                    <jats:italic>Lactobacillus<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1002\/anie.202525914","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:13:20Z","timestamp":1773004400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Biomimetic Nanoparticles With Targeted Delivery of Chlorothiazide for the Treatment of Inflammatory Bowel Disease"],"prefix":"10.1002","volume":"65","author":[{"given":"Yujie","family":"Shi","sequence":"first","affiliation":[{"name":"Anhui Key Laboratory of Infection and Immunity Center For Innovation in Basic Medical Sciences Bengbu Medical University  Bengbu Anhui China"},{"name":"Department of Pathology School of Basic Medical Sciences Bengbu Medical University  Bengbu Anhui 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