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.

中文翻译：

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口服施用以葫芦[8]尿嘧啶复合物封端的介孔二氧化硅，可通过靶向肠道菌群来抵抗结肠炎和改善肠道稳态。

理由：炎症性肠病（IBD）仍在等待创新的治疗方法，该方法可在提高肠道动态平衡的同时最大程度地提高结肠中特定部位药物的释放效率。方法：在本文中，我们介绍了多层包被的介孔二氧化硅（MS），在肠道菌群产生的偶氮还原酶存在下，该物质在结肠中特异性释放有效载荷药物，并同时使微生物组的色氨酸代谢恢复活力，从而诱导芳基烃的活化受体（AHR）具有增强的抗炎作用。通过使用葫芦[8]尿素（CB [8]）作为超分子“手铐”来制备MS，以将壳聚糖/透明质酸多层体组装在介孔二氧化硅核的外围。结果令人惊讶的是，尽管MS在酸性和中性pH值下均保持稳定，但它们对连二亚硫酸盐（一种偶氮还原剂，可替代体外模拟特定的偶氮还原酶的环境）表现出出色的响应性。与游离形式的药物相比，氢化可的松载药在体内显示出优化的药物在结肠粘膜中的蓄积，并使体内上消化道的过早释放最小化成像和生物分布研究。在具有增强的结肠上皮屏障完整性，升高的AHR激动剂水平和调节的炎性细胞因子产生的小鼠中，在葡聚糖硫酸钠诱导的结肠炎中证实了MS的增强的治疗作用。此外，16S rRNA分析表明，通过MS可以部分纠正大肠杆菌小鼠的肠道稳态。结论：这种新型的药物输送系统利用色氨酸官能化的壳聚糖与CB [8]预先复合，并在介孔二氧化硅纳米颗粒表面偶氮苯官能化的透明质酸自组装，为IBD治疗提供了一种协同肠道菌群靶向方法。