{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:19:15Z","timestamp":1788427155058,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Smart Molecules"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug\u2010induced liver injury (DILI) is a complex and intractable disease because existing anti\u2010oxidate therapies in clinic fail to modulate multiple pathological pathways concurrently. Here, we present a direction\u2010aware framework that integrates disease\u2010network analysis, AI\u2010guided molecular screening, and self\u2010assembled nanomedicine design for precise protection of DILI. Time\u2010resolved transcriptomic profiling of DILI identifies two complementary repair axes: the suppression of cytokine\u2010cytokine receptor signaling for inflammation control together with the activation of glutathione biosynthesis for antioxidant defense. Guided by these DILI\u2010driven mechanisms, we develop a dual\u2010constraint deep\u2010learning model that jointly evaluates the interaction between therapeutic molecules and disease targets, enabling the identification of candidate molecules whose biological effects match the desired intervention. Through independent screening from FDA\u2010approved active pharmaceutical ingredients pool, we explore hesperidin (HES) and ursodeoxycholic acid (UDCA) as combination molecules capable of self\u2010assembling into uniform nanomedicines (HUNMs) with predicted biological activities. Flash nanocomplexation\u2010based engineering of HES and UDCA produces stable carrier\u2010free nanocrystals with improved aqueous dispersibility. In an acetaminophen\u2010challenged DILI mice, HUNMs alleviate hepatic injury, suppress inflammatory responses, restore glutathione homeostasis, and accelerate liver recovery. Together, our insights highlight an AI\u2010native strategy that harnesses smart molecules to develop a precise and translatable nanomedicine for efficient management of DILI and other complex diseases.<\/jats:p>","DOI":"10.1002\/smo2.70101","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:59:55Z","timestamp":1788425995000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AI\u2010enabled engineering of hesperidin\/ursodeoxycholic acid nanomedicine for synergistic treatment of drug\u2010induced liver injury"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2516-3521","authenticated-orcid":false,"given":"Kai","family":"Xiao","sequence":"first","affiliation":[{"name":"School of Medicine South China University of Technology  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Electronic and Computer Engineering Peking University  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7031-5254","authenticated-orcid":false,"given":"Haoyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Urology Inner Mongolia Autonomous Region People's Hospital  Hohhot Inner Mongolia China"},{"name":"Institutes of Biomedical Sciences Inner Mongolia University  Hohhot Inner Mongolia China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyuan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Urology Inner Mongolia Autonomous Region People's Hospital  Hohhot Inner Mongolia China"},{"name":"Institutes of Biomedical Sciences Inner Mongolia University  Hohhot Inner Mongolia China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaowen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine South China University of Technology  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9126-3589","authenticated-orcid":false,"given":"Ziping","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiming","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"},{"name":"Department of General Surgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Center for Orthopedic Surgery The Third Affiliated Hospital of Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9324-1450","authenticated-orcid":false,"given":"Quanxin","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Center for Orthopedic Surgery The Third Affiliated Hospital of Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5776-7366","authenticated-orcid":false,"given":"Sigen","family":"A","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary\u2010Pancreatic\u2010Splenic Surgery Inner Mongolia Autonomous Region People's Hospital  Hohhot Inner Mongolia China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Center for Orthopedic Surgery The Third Affiliated Hospital of Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huayi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of General Surgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Urology Inner Mongolia Autonomous Region People's Hospital  Hohhot Inner Mongolia China"},{"name":"Institutes of Biomedical Sciences Inner Mongolia University  Hohhot Inner Mongolia China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5243-042X","authenticated-orcid":false,"given":"Dan","family":"Shao","sequence":"additional","affiliation":[{"name":"School of Medicine South China University of Technology  Guangzhou Guangdong China"},{"name":"State Key Laboratory of Oral Diseases &amp; 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