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Introduction: Schematic illustration of the synthetic protocols and therapeutic mechanisms of HA-BSA@DS. We report a pioneering endogenous GSH-responsive nanoplatform, meticulously engineered for the controlled release of hydrogen sulfide (H 2 S) within inflamed intestinal tissues, thus offering a new avenue for gaseous intervention in chronic enteritis. [Display omitted] • Here, we report a nano-delivery platform for effective intervention in UC with H 2 S release in response to intracellular GSH. • Nano-platform can improve inflammatory response by regulating Nrf2/NF-κB/iNOS/NLRP3 signaling pathway. • Nanoparticles can modulate the homeostasis of gut microbiota. • Tese nanoparticles achieve gaseous intervention for the intervention of intestinal inflammation. Overproduction of reactive oxygen species (ROS) is a primary cause of chronic intestinal inflammation, controlled nanosequence-like drugs with GSH-responsive release have become a new focus in scavenging ROS and treating inflammation. Here, we report an endogenous GSH-responsive nanoplatform, meticulously engineered for the controlled release of hydrogen sulfide (H 2 S) within inflamed intestinal tissues, thus offering a new avenue for gaseous intervention against chronic enteritis. Diallyl trisulfide (DS) as molecular H 2 S donors was conjugated into sulfhydrylated bovine serum albumin (BSA·SH) through a 'thio-ene' click chemistry reaction, leading to the synthesis of the BSA@DS polymer. This substrate was subsequently coated with hyaluronic acid, yielding HA-BSA@DS nanoparticles. As sulfide bonds in DS are responsive to intracellular GSH to release H 2 S and HA achieves inflamed site-targeted release specifically towards CD44-overexpressed inflamed tissues, these nanoparticles attenuate pro-inflammatory cytokine outputs while concurrently upregulate anti-inflammatory factors, thus mitigating cellular oxidative perturbations and inflammatory responses in inflamed cells. Moreover, upon oral administration, these nanoparticles exhibit profound anti-inflammatory efficacy via the TLR4/MD2/MyD88/NF-κB/iNOS signal pathway and modulating the homeostasis of intestinal microbiota in a mouse model with colitis. Consequently, this convenient and targeted oral nanoparticle effectively enables gaseous multiple intervention at the inflammatory site, providing a favorable theoretical basis for subsequent oral formulations in the treatment of related inflammation. [ABSTRACT FROM AUTHOR]

Na-K-ATPase located on the basolateral membrane (BLM) of intestinal epithelial cells provides a favorable intracellular Na + gradient to promote all Na dependent co-transport processes across the brush border membrane (BBM). Down-regulation of Na-K-ATPase activity has been postulated to alter the absorption via Na-solute co-transporters in human inflammatory bowel disease (IBD). Further, the altered activity of a variety of Na-solute co-transporters in intact villus cells has been reported in animal models of chronic enteritis. But the molecular mechanism of down-regulation of Na-K-ATPase is not known. In the present study, using a rabbit model of chronic intestinal inflammation, which resembles human IBD, Na-K-ATPase in villus cells was shown to decrease. The relative mRNA abundance of α -1 and β -1 subunits was not altered in villus cells during chronic intestinal inflammation. Similarly, the protein levels of these subunits were also not altered in villus cells during chronic enteritis. However, the BLM concentration of α-1 and β -1 subunits was diminished in the chronically inflamed intestinal villus cells. An ankyrin–spectrin skeleton is necessary for the proper trafficking of Na-K-ATPase to the BLM of the cell. In the present study, ankyrin expression was markedly diminished in villus cells from the chronically inflamed intestine resulting in depolarization of ankyrin-G protein. The decrease of Na-K-ATPase activity was comparable to that seen in ankyrin knockdown IEC-18 cells. Therefore, altered localization of Na-K-ATPase as a result of transcriptional down-regulation of ankyrin-G mediates the down-regulation of Na-K-ATPase activity during chronic intestinal inflammation. [ABSTRACT FROM AUTHOR]