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Although lipophagy selectively degrades LDs to release free fatty acids (FFAs) and remodel lipid homeostasis, leveraging this process to overcome lipid\u2010buffering ferroptosis resistance remains largely unexplored. Here, we report LipoTIDE (Lipophagy\u2010Tuning Induced Death Enhancer), a self\u2010reinforcing nanoplatform that primes lipophagy\u2010primed ferroptosis by coupling precise lipophagy activation with catalytic ROS generation to dismantle LDs\u2010mediated metabolic defenses in tumors. LipoTIDE co\u2010delivers ultrasmall Pt\n                    <jats:sub>3<\/jats:sub>\n                    Co nanoalloys and tamoxifen within a pH\u2010responsive amphiphilic polymer, enabling tumor\u2010targeted disassembly and localized therapeutic amplification. Triggered by the tumor acidity, LipoTIDE releases Pt\n                    <jats:sub>3<\/jats:sub>\n                    Co nanoalloys for multiple catalytic activities and tamoxifen for initiating lipophagy and decreasing pH value, establishing a self\u2010reinforcing loop that sustains lipophagy and ferroptosis. Additionally, FFAs from lipophagy, together with the Pt\n                    <jats:sub>3<\/jats:sub>\n                    Co nanoalloys, resensitize resistant cancer cells to Pt\n                    <jats:sub>3<\/jats:sub>\n                    Co\u2010catalyzed ROS, thereby amplifying ferroptosis. Consequently, LipoTIDE precisely disrupts lipid homeostasis, triggers robust ferroptotic tumor suppression, and exhibits minimal systemic toxicity. These findings establish lipophagy\u2010primed ferroptosis as a generalizable and actionable strategy for dismantling lipid\u2010buffering defenses of tumors.\n                  <\/jats:p>","DOI":"10.1002\/anie.2688720","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T19:24:27Z","timestamp":1784834667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Self\u2010Reinforcing LipoTIDE Nanoplatform That Overcomes Lipid\u2010Buffering Ferroptosis Resistance for Enhanced Cancer Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Guoqiang","family":"Guan","sequence":"first","affiliation":[{"name":"National Center for Translational Medicine (Shanghai) Hefei Branch, Institute of Pharmaceutics, School of Pharmacy, Anhui University of Chinese Medicine Anhui Academy of Chinese Medicine  Hefei Anhui China"},{"name":"Joint R&amp;D Center for Structural Imaging and Metabolic\u2010Immunoregulatory Technologies in Integrated Traditional Chinese and Modern Medicine Shanghai Jiao Tong University  Shanghai China"},{"name":"State Key Laboratory of Chemo\/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering Hunan University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-4408","authenticated-orcid":false,"given":"Xi","family":"Hu","sequence":"additional","affiliation":[{"name":"National Center for Translational Medicine (Shanghai) Hefei Branch, Institute of Pharmaceutics, School of Pharmacy, Anhui University of Chinese Medicine Anhui Academy of Chinese Medicine  Hefei Anhui China"},{"name":"Joint R&amp;D Center for Structural Imaging and Metabolic\u2010Immunoregulatory Technologies in Integrated Traditional Chinese and Modern Medicine Shanghai Jiao Tong University  Shanghai 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Translational Medicine (Shanghai) Hefei Branch, Institute of Pharmaceutics, School of Pharmacy, Anhui University of Chinese Medicine Anhui Academy of Chinese Medicine  Hefei Anhui China"},{"name":"Joint R&amp;D Center for Structural Imaging and Metabolic\u2010Immunoregulatory Technologies in Integrated Traditional Chinese and Modern Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Chen","sequence":"additional","affiliation":[{"name":"National Center for Translational Medicine (Shanghai) Hefei Branch, Institute of Pharmaceutics, School of Pharmacy, Anhui University of Chinese Medicine Anhui Academy of Chinese Medicine  Hefei Anhui China"},{"name":"Joint R&amp;D Center for Structural Imaging and Metabolic\u2010Immunoregulatory Technologies in Integrated Traditional Chinese and Modern Medicine Shanghai Jiao Tong University  Shanghai 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