Glutathione-responsive nanoplatforms trigger gaseous intervention of intestinal inflammation through TLR4/MD2/MyD88/NF-κB/iNOS pathway activation and gut microbiota modulation

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 (H2S) within inflamed intestinal tissues, thus offering a new avenue for gaseous intervention against chronic enteritis. Diallyl trisulfide (DS) as molecular H2S 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 H2S 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.