A "One-Stone-Three-Birds" Inspired Nanoplatform for Multitargeted Ulcerative Colitis Therapy via Combined Aryl Hydrocarbon Receptor Activation and Reactive Oxygen Species Scavenging.

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.