Engineered Probiotics Enable Targeted Gut Delivery of Dual Gasotransmitters for Inflammatory Bowel Disease Therapy

Abstract Inflammatory bowel disease (IBD) remains an incurable condition, often accompanied by high rates of anxiety and depression, further diminishing the quality of life of patients. Endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H₂S), exhibit potent anti‐inflammatory and immunomodulatory effects. However, their therapeutic application is limited by challenges in targeted delivery to affected tissues. Here, we propose a novel strategy for targeted gut delivery of CO/H 2 S through engineering Escherichia coli Nissle 1917 (EcN) with CO/H 2 S‐releasing copolymer (POSR) loading. This engineered probiotic (POSR@EcN) enhances EcN colonization in the intestine and enables controlled, localized release of CO/H 2 S at inflamed sites. The release of CO/H 2 S modulates inflammation, restores intestinal barrier integrity, and reshapes gut microbiota by promoting beneficial bacteria and increasing short‐chain fatty acids production, effectively alleviating IBD symptoms. Notably, targeted CO/H 2 S delivery also elevates neuroprotective metabolites like indoleacetic acid and γ‐aminobutyric acid, reducing neuroinflammation via the gut‐brain axis and mitigating anxiety‐ and depression‐like behaviors in IBD mice. This approach highlights the potential of EcN as a probiotic carrier for the targeted delivery of gasotransmitters, offering a promising strategy for IBD treatment.