An Oral H₂S Responsive Cu_5.4O Nanozyme Platform with Strong ROS/H₂S Scavenging Capacity for the Treatment of Colitis

Inflammatory bowel disease involves excess reactive oxygen species (ROS) and hydrogen sulfide (H₂S) at inflammatory sites. Nanozyme-mediated ROS and H₂S scavenging therapy is promising for colitis treatment. Here, we synthesized a multiple ROS scavenging Cu_5.4O nanoparticle and first explored its H₂S scavenging capacity. Chitosan oligosaccharide modified with alpha-lipoic acid was coated on the nanoparticles to further enhance the H₂S scavenging capacity. Furthermore, calcium alginate was coated on the surface to develop an oral nanoplatform (Cu_5.4O@SAG) possessing dual-pH/H₂S-responsive release characteristics. Importantly, Cu_5.4O@SAG exhibited enrichment at the colonic inflammation site and relieved the inflammatory index, containing the recovery of colon length, spleen index, liver index, and body weight, as well as inflammatory cell infiltration. In vivo and in vitro experiments revealed the dual ROS and H₂S scavenging capacities of the nanoplatform. Additionally, Cu_5.4O@SAG regulated tight junctions, mucus layers, and gut microbiota, which was accompanied by the downregulation of inflammatory cytokines. Notably, Cu_5.4O@SAG also had excellent biocompatibility. In conclusion, this oral multiple-scavenging nanozyme platform provides a new and safe paradigm for the development of nanozymes for colitis treatment.