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RATIONALE Inflammatory bowel diseases (IBDs) are still awaiting innovative treatments that can maximize the efficiency of site-specific drug release in the colon while enhancing intestinal homeostasis. METHODS Herein, we present multilayer-coated mesoporous silica (MSs) which release payload drugs specifically in the colon tract in the presence of azoreductase produced by the gut microbiota, and simultaneously rejuvenate the tryptophan metabolism of the microbiome to induce activation of the aryl hydrocarbon receptor (AHR) for increased anti-inflammatory effects. The MSs were prepared by using cucurbit[8]uril (CB[8]) as a supramolecular "handcuff" to assemble chitosan/hyaluronic acid multilayers on the periphery of a mesoporous silica core. RESULTS Strikingly, although MSs remained fairly stable in both acidic and neutral pH, they exhibited excellent responsiveness towards dithionite, an azo-reducing agent employed as a substitute to mimic the specific azoreductase environment in vitro. In comparison with the drug in its free form, hydrocortisone-loaded MSs showed optimized accumulation of therapeutics in the colonic mucosa with minimized premature release in the upper gastrointestinal tract in in vivo imaging and biodistribution studies. The enhanced therapeutic effects of MSs were confirmed in dextran sodium sulfate-induced colitis in mice with promoted colonic epithelial barrier integrity, elevated level of AHR agonists and modulated production of inflammatory cytokines. Furthermore, 16S rRNA analysis showed that the disrupted gut homeostasis of colitic mice was partly corrected by MSs. CONCLUSION This novel drug delivery system using self-assembly of tryptophan-functionalized chitosan, which was precomplexed with CB[8], and azobenzene-functionalized hyaluronic acid on the surface of mesoporous silica nanoparticles provides a synergistic gut microbiota-targeting approach for IBD therapy.