Oral probiotic biotherapies hold significant promise for addressing intestinal inflammatory disorders. Nonetheless, due to the challenging pathological microenvironment of the gastrointestinal tract, it is difficult to achieve deliver probiotics in an inflammation-targeted manner while improving their intestinal colonization and minimizing the impact of gastrointestinal environment on their vitality. To address this, an innovative probiotics oral delivery system (EcN-Apt@HG) against ulcerative colitis (UC) was developed by conjugating IL-6 aptamer to the surface of EcN and subsequently encapsulating the probiotics in a hydrogel consisting of aldehyde-functionalized chondroitin sulfate (CS) and Poly(amidoamine) (PAMAM). As expected, the encapsulated EcN demonstrated resistance to gastrointestinal conditions, and the colonization duration of probiotics in the colon was enhanced via the preferential adhesion effect of IL-6 aptamer on the inflammatory site. The EcN-Apt@HG system restored the damaged mucosal layer, suppressed hyperactive immune responses, and reshaped the dysbiosis of intestinal microflora, thereby synergistically alleviating dextran sulfate sodium (DSS)-induced colitis. Notably, EcN-Apt@HG significantly alleviated depression-like behaviors and cognitive impairment in colitis mice through gut-brain axis interaction. This approach provides a simple and promising strategy for inflammation-targeted delivery of probiotics to the intestine and shows great potential for UC therapy and associated cognitive disorders.