Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis

The cell-specific functions of nitric oxide(NO)in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis.While most biomaterials show promise by eliciting the characteristics of NO,the insufficient storage,burst release,and pro-inflammatory side effects of NO remain as challenges.Herein,we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles(MONs)that improve the storage and sustained release of NO,broadening the therapeutic window of NO-based therapy against colitis.The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone(Dex)in the intestinal microenvironment,specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation.Mechanistically,such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange.Specifically,the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid,even after delayed treatment.Together,our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.