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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 \u201cone-stone-three-birds\u201d outcome\u2014attenuating inflammation, repairing mucosa, and rebalancing microbiota\u2014providing new experimental evidence and theoretical support for ulcerative colitis therapy.<\/jats:p>","DOI":"10.34133\/bmr.0356","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T07:45:21Z","timestamp":1775029521000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":1,"title":["A \u201cOne-Stone-Three-Birds\u201d Inspired Nanoplatform for Multitargeted Ulcerative Colitis Therapy via Combined Aryl Hydrocarbon Receptor Activation and Reactive Oxygen Species Scavenging"],"prefix":"10.34133","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2393-8128","authenticated-orcid":false,"given":"Kai","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Pharmacy, \rThe First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."},{"name":"School of Pharmacy, \rXi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelin","family":"Guan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, \rXi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, \rXi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \rThe First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \rThe First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiyu","family":"You","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \rThe First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanming","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, \rThe First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00966-2"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2025.1610435"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2025.1565082"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2025.05.006"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00585-5"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-024-01750-y"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00430-8"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06880"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2187"},{"issue":"3","key":"e_1_3_4_11_2","first-page":"353","article-title":"Activation of aryl hydrocarbon receptor (AhR) alleviates depressive-like behaviors in LPS-induced mice","volume":"76","author":"Wang MY","year":"2024","unstructured":"Wang MY, Li JM, Wu YL, Zhang Y, Hu T, Su WJ, Feng JF, Jiang CL. 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