A "One-Stone-Three-Birds" Inspired Nanoplatform for Multitargeted Ulcerative Colitis Therapy via Combined Aryl...

In the pathogenesis of ulcerative colitis, inflammatory responses, mucosal injury, and gut dysbiosis form a mutually reinforcing network that perpetuates disease progression. Current clinical interventions can rarely modulate these pathological modules simultaneously, underscoring the urgent need for more effective therapeutic strategies. Here, we report a dual-functional nanotherapy that couples aryl hydrocarbon receptor (AhR) activation with on-site reactive oxygen species (ROS) scavenging. An amphiphilic copolymer, HA-TK-LA (HTL), was synthesized by grafting lipoic acid (LA) to hyaluronic acid (HA) via a ROS-cleavable thioketal (TK) linker. The copolymer self-assembles into ~130-nm nanoparticles that encapsulate the natural AhR ligand indole-3-acetic acid (IAA) with a high loading efficiency of 73%. The resulting IAA@HTL nanoparticles exhibit ROS/glutathione-triggered drug release and are actively taken up by inflamed intestinal epithelial cells and M1 macrophages through CD44-mediated endocytosis, leading to suppressed epithelial apoptosis and macrophage repolarization toward an anti-inflammatory phenotype. In dextran sulfate sodium-induced murine colitis, IAA@HTL specifically accumulates in the inflamed colon and markedly alleviates disease activity. Mechanistically, IAA and LA released from the nanoparticles synergistically activate aryl hydrocarbon receptor/cytochrome P450 family 1 subfamily A member 1 and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling, skew macrophages toward an anti-inflammatory state, dampen proinflammatory cytokine release, and reinforce the mucosal barrier by up-regulating tight-junction proteins and interleukin-22 secretion. As inflammation subsides and mucosal integrity is restored, the gut microbiota gradually returns to homeostasis. Collectively, this study establishes a ROS-scavenging and AhR-activating nanodelivery system that achieves a "one-stone-three-birds" outcome-attenuating inflammation, repairing mucosa, and rebalancing microbiota-providing new experimental evidence and theoretical support for ulcerative colitis therapy.