{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:02:01Z","timestamp":1791385321024,"version":"4.3.3"},"reference-count":29,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82002501"],"award-info":[{"award-number":["82002501"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103401"],"award-info":[{"award-number":["82103401"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["52173150"],"award-info":[{"award-number":["52173150"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515030145"],"award-info":[{"award-number":["2024A1515030145"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Ferroptosis has emerged as a critical mechanism in overcoming drug resistance in various tumors; however, its role in gemcitabine\u2010resistant pancreatic ductal adenocarcinoma (PDAC) has not been thoroughly explored. Additionally, the effectiveness of ferroptosis in many cancer therapies has been limited. In our study, we found that GPX4 is upregulated in gemcitabine\u2010resistant (GR) PDAC patient tissues and cell lines. Notably, inhibiting GPX4 can reverse gemcitabine resistance in PDAC through the induction of ferroptosis, highlighting it as a potential therapeutic target. To address this, we developed a novel nanomedicine, GSH\u2010depleted and ferroptosis\u2010induced (FiN), designed to encapsulate and deliver the GPX4 inhibitor RSL3, resulting in a dual ferroptosis\u2010induced nanomedicine (DFiN). In a PDAC patient\u2010derived xenograft (PDX) mouse model exhibiting gemcitabine resistance, DFiN demonstrated significant accumulation in GR PDAC tumors, leading to a reduction in intracellular GSH levels and inhibition of GPX4. This dual action promoted lipid peroxidation and synergistically induced ferroptosis, effectively reversing gemcitabine resistance. Both in vitro and in vivo experiments confirmed that DFiN is effective in overcoming gemcitabine resistance in GR PDAC cells and PDX tumors, with minimal toxicity observed. This study presents a promising strategy for addressing drug resistance in cancer therapy.<\/jats:p>","DOI":"10.1002\/adhm.202503694","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T06:23:09Z","timestamp":1766816589000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synergistic Induction of Ferroptosis by GPX4 Inhibitor and GSH\u2010Depleted Nanoparticles Effectively Reverses Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma PDX Model"],"prefix":"10.1002","volume":"15","author":[{"given":"Chen\u2010Song","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Hematologic Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010sen University Cancer Center  Guangzhou China"},{"name":"Bioscience and Biomedical Engineering Thrust The Hong Kong University of Science and Technology (Guangzhou)  Nansha Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Department of Liver Surgery Sun Yat\u2010sen University Cancer Center Guangzhou  Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Stem Cells and Tissue Engineering Ministry of Education Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Hao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie\u2010Qin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Guangzhou Women and Children's Medical Center Guangdong Provincial Clinical Research Center for Child Health Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An\u2010Da","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2010Tai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-3435","authenticated-orcid":false,"given":"Jun","family":"Wu","sequence":"additional","affiliation":[{"name":"Bioscience and Biomedical Engineering Thrust The Hong Kong University of Science and Technology (Guangzhou)  Nansha Guangzhou China"},{"name":"Division of Life Science The Hong Kong University of Science and Technology  Hong Kong, SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Yu","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"7","article-title":"Cancer Statistics","volume":"70","author":"Siegel R. L.","year":"2020","journal-title":"CA\u2010A Cancer Journal for Clinicians"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70172-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1304369"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73455"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1171362"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114351"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2016.12.010"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1979"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-3855"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115892"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.03.002"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.65480"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.3c04293"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01419-2"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0829-z"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.010"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/972913"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2004.03.014"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0005-x"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2022.100916"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-20-341"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-022-01530-y"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2019.11.029"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.158"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2016.164"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202206286"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202503694","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adhm.202503694","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202503694","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:00:37Z","timestamp":1774620037000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.202503694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,26]]},"references-count":29,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/adhm.202503694"],"URL":"https:\/\/doi.org\/10.1002\/adhm.202503694","archive":["Portico"],"relation":{},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,26]]},"assertion":[{"value":"2025-07-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e03694"}}