A “One-Stone-Three-Birds” Inspired Nanoplatform for Multi-Targeted Ulcerative Colitis Therapy via Combined AhR Activation and ROS Scavenging

In the pathogenesis of ulcerative colitis (UC), inflammatory responses, mucosal injury, and gutdysbiosis form a mutually reinforcing network that perpetuates disease progression. Current clinicalinterventions can rarely modulate these pathological modules simultaneously, underscoring theurgent need for more effective therapeutic strategies. Here, we report a dual-functional nano-therapythat 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 exhibitROS/glutathione (GSH)-triggered drug release, and are actively taken up by inflamed intestinalepithelial cells and M1 macrophages through CD44-mediated endocytosis, leading to suppressedepithelial apoptosis and macrophage repolarization toward an anti-inflammatory phenotype. Indextran sulfate sodium (DSS)-induced murine colitis, IAA@HTL specifically accumulates in theinflamed colon and markedly alleviates disease activity. Mechanistically, IAA and LA releasedfrom the nanoparticles synergistically activate AhR/CYP1A1 and Nrf2/HO-1 signaling, skewmacrophages toward an anti-inflammatory state, dampen pro-inflammatory cytokine release, andreinforce the mucosal barrier by up-regulating tight-junction proteins and IL-22 secretion. Asinflammation subsides and mucosal integrity is restored, the gut microbiota gradually returns tohomeostasis. Collectively, this study establishes a ROS-scavenging and AhR-activating nano-delivery system that achieves a “one-stone-three-birds” outcome—attenuating inflammation,repairing mucosa, and rebalancing microbiota—providing new experimental evidence andtheoretical support for UC therapy.Keywords: ulcerative colitis, AhR receptor, reactive oxygen species, active targeting, macrophages