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In this study, we constructed a dual\u2010targeting polymeric micelle (S&amp;A@TPD\/HG PMs), co\u2010delivering sorafenib (SOR), and artesunate (ART) to achieve synergistic ferroptosis\u2010based therapy against HCC. The micelle features a hyaluronic acid (HA) shell functionalized with glycyrrhetinic acid (GA) for active dual targeting to CD44 and GA receptors overexpressed on HCC cells; while its triphenylphosphonium (TPP)\u2010decorated inner core facilitates mitochondrial anchoring and co\u2010conveys the drugs, enabling stepwise subcellular targeting. Compared with free drugs or single\u2010drug\u2010loaded micelles, S&amp;A@TPD\/HG PMs effectively induced mitochondrial damage by depleting glutathione (GSH), and downregulating GSH peroxidase 4 (GPX4) expression to disrupt the mitochondrial antioxidant defense system, elevating intracellular Fe\n                    <jats:sup>2+<\/jats:sup>\n                    to increase reactive oxygen species (ROS) and lipid peroxidation (LPO) production, thereby compromising mitochondrial redox homeostasis and potentiating ferroptosis jointly. This ferroptosis\u2010inducing activity yielded potent in vivo antitumor efficacy in Huh\u20107 tumor\u2010bearing nude mice, with a tumor inhibition rate of 74.23% and minimal systemic toxicity. Collectively, the organelle\u2010specific targeting combined with co\u2010delivery of synergistic drug pairs represents a promising strategy for combating malignancies and provides a blueprint for the rational design of multifunctional nanosystems.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71875","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T03:31:29Z","timestamp":1792553489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual\u2010Targeting Nanomicelles Co\u2010Loading Sorafenib and Artesunate Combats Hepatocellular Carcinoma via the Synergistically Enhanced Ferroptosis Strategy"],"prefix":"10.1002","author":[{"given":"Wangjing","family":"Lu","sequence":"first","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxia","family":"Mi","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazhen","family":"Luo","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Guo","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xupeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"Pharmacy Department Shanghai Integrated Traditional Chinese and Western Medicine Hospital  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8804-1290","authenticated-orcid":false,"given":"Yan","family":"Xie","sequence":"additional","affiliation":[{"name":"Research Center for Health and Nutrition School of Public Health Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010024\u201002957\u20105"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000546574"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000551631"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215880"},{"issue":"6","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15061680","article-title":"Systemic Therapy for Advanced Hepatocellular Carcinoma: Current Stand and Perspectives","volume":"15","author":"Girardi D. 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