Intestinal Barrier Repair‐Based Copper‐Kaempferol Nanocomplexes Regulates Gut‐Liver Axis Homeostasis

Inflammatory bowel disease (IBD) and its frequent hepatic complication, metabolic-associated steatohepatitis (MASH), are intrinsically linked through the dysregulated gut-liver axis, with intestinal barrier dysfunction serving as a central pathological driver. Coordinated therapy that restores barrier integrity and interrupts pathogenic gut-liver crosstalk remains a significant challenge. To address this, a colon-targeted delivery system based on sodium alginate microspheres is developed for loading copper-kaempferol nanocomplexes (CuK@SA). Upon oral administration, this system prolongs the retention and release of CuK NCs in the colon. Through scavenging reactive oxygen and nitrogen species (ROS/RNS), regulating macrophage polarization, improving microbial homeostasis, and enhancing tight junction protein expression, it multi-dimensionally restores intestinal barrier integrity and effectively blocks the translocation of endotoxins to the liver via the gut-liver axis. In mouse models of dextran sulfate sodium (DSS)-induced colitis and high-fat-diet-induced MASH, CuK@SA significantly alleviates intestinal inflammation, repairs barrier structure, and simultaneously improves hepatic steatosis and inflammatory responses. This work provides a novel strategy for synchronously targeting IBD and its systemic complications through modulation of the gut-liver axis.