Copper–luteolin nanocomplexes for Mediating multifaceted regulation of oxidative stress, intestinal barrier, and gut microbiota in inflammatory bowel disease

Oxidative stress, dysbiosis, and immune dysregulation have been confirmed to play pivotal roles in the complex pathogenesis of inflammatory bowel disease (IBD). Herein, we design copper ion–luteolin nanocomplexes (CuL NCs) through a metal–polyphenol coordination strategy, which plays a multifaceted role in the amelioration of IBD. The fabricated CuL NCs function as therapeutic agents with exceptional antioxidant and anti-inflammatory capabilities because of their great stability and capacity to scavenge reactive oxygen species (ROS). It can effectively modulate the inflammatory microenvironment including facilitating the efficient reduction of pro-inflammatory cytokine levels, protecting intestinal epithelial cells, promoting mucosal barrier repair and regulating intestinal microbiota. In addition, CuL NCs have been found to enhance cellular antioxidant and anti-inflammatory capacities by regulating the nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1) oxidative stress pathway and nuclear factor kappa B (NF-κB) signaling pathway, respectively. Notably, CuL NCs demonstrate significant prophylactic and therapeutic efficacy in mouse models with typical IBD, including ulcerative colitis (UC) and Crohn's disease (CD). This study provides a new approach for building multifaceted therapeutic platforms for natural products to treat IBD. Copper ion-luteolin nanoparticle (CuL NCs) has been developed successfully, which show notable therapeutic effects in both DSS and TNBS-induced IBD models by modulation of the inflammatory microenvironment at the damaged sites of the intestine by scavenging excess ROS, regulating NF-κB/Nrf2 stress pathways and gut microbiota. • Copper ions-luteotein nanocomplexes (CuL NCs) show greater stability and bioavailability. • CuL NCs activate the Nrf2 pathway for antioxidant defense and regulating the inflammatory microenvironment. • CuL NCs restore intestinal barrier function and promote a healthier gut microbiome.