Probiotic–Drug Conjugates Achieve Synchronized Site-Specific Probiotic Colonization and On-Demand Drug Release against Ulcerative Colitis and Its Complication

The oral surface-modified probiotic therapy, capable of maintaining activity and adhesion of probiotics under harsh gastrointestinal conditions, is effective in treating ulcerative colitis (UC). However, the currently reported surface-modified probiotics suffer from poor selective colonization at a lesion site and limited codelivery capability with other treatment modalities due to different physicochemical properties. Herein, we develop triggerable probiotic-drug conjugates that enable synchronous site-specific probiotic colonization and on-demand drug release for the treatment of UC and its complication. Specifically, the conjugates are composed of probiotic <i>Escherichia coli</i> Nissle 1917 encapsulated with the adhesive tannic acid-ferric inner layer and the reactive oxygen species (ROS)-responsive thioether-bridged pterostilbene-lipid outer coating. Following oral administration, the pathological high-level ROS can trigger the adaptable release of anti-inflammatory pterostilbene and adhesive probiotics from conjugates in the inflamed colon. The targeted colonization of adhesive probiotics, combined with pterostilbene at the lesion site in a synchronous manner, achieves inflammation suppression and sustained gut microbiota modulation. In both mouse models of UC and associated complications, this conjugate demonstrates significant therapeutic and prophylactic efficacy, highlighting its translational potential for clinical combined applications in gastrointestinal disorders.