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Regrettably, clinical antidepressants exhibit unsatisfactory therapeutic efficacy in IBD\u2010associated psychosocial disturbances, primarily attributed to the inherent intestinal disorders and intricate bidirectional relationship between the gut and the brain. Herein, we report a metal\u2013polyphenol\u2010based antidepressant to alleviate mental disorders in dextran sulfate sodium\u2010induced experimental acute colitis mice via modulating the microbiota\u2013gut\u2013brain axis. The antidepressant, termed CSMTC, comprises a core of melittin\u2010encapsulated natural antioxidant enzymes (i.e., catalase and superoxide dismutase) and a protective shell composed of tannic acid\u2013cerium ion network. Upon oral administration to colitis mice, CSMTC can effectively restore colonic redox balance, reinforce the intestinal barrier, modulate gut microbiota composition, maintain the blood\u2013brain barrier integrity, and regulate systemic immune responses. Notably, behavioral test results reveal that CSMTC significantly alleviates the colitis\u2010associated mental disorder (e.g., depression\u2010like behavior) via the microbiota\u2013gut\u2013brain axis by reducing neuroinflammation, enhancing hippocampal neural plasticity, modulating hippocampal immune responses, and restoring neurotransmitter homeostasis. This work may have implications for the development of new nanodrugs for treating inflammation\u2010associated complications.<\/jats:p>","DOI":"10.1002\/adma.202410993","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T02:16:18Z","timestamp":1733192178000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Metal\u2013Polyphenol\u2010Based Antidepressant for Alleviating Colitis\u2010Associated Mental Disorders"],"prefix":"10.1002","volume":"37","author":[{"given":"Zihao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering Jiangsu Key Laboratory for Biomaterials and Devices School of Biological Science and Medical Engineering Southeast University  Nanjing 211189 P. R. 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