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Ferroptosis\u2010based therapies provide a promising strategy for eliminating these resistant cells. Here, we demonstrate that cytarabine chemotherapy promotes lipid droplet (LD) accumulation in BM\u2010resident LCs, thereby conferring resistance to ferroptosis. Based on these findings, we developed a biomimetic liposome (REM@HLipo) co\u2010encapsulating RSL3 (a ferroptosis inducer), elacytarabine (a cytarabine prodrug), and metformin (an LD disruptor) to enhance chemo\u2010ferroptosis therapy against leukemia. Upon targeted delivery to BM\u2010resident LCs, metformin disrupts LDs and increases the availability of polyunsaturated fatty acids (PUFAs) for oxidation, thereby sensitizing LCs to RSL3\u2010induced ferroptosis. This effect synergizes with cytarabine to exert potent cytotoxicity against BM\u2010resident LCs in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) mouse models. Moreover, REM@HLipo significantly reduces leukemia stem cell populations in AML models. This study presents a novel chemo\u2010ferroptosis therapeutic regimen for leukemia management.<\/jats:p>","DOI":"10.1002\/adma.202515716","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:43:41Z","timestamp":1773301421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipid Droplet\u2010Targeted Biomimetic Liposomes Potentiate Chemo\u2010Ferroptosis Therapy in Leukemia"],"prefix":"10.1002","volume":"38","author":[{"given":"Xinyu","family":"Wang","sequence":"first","affiliation":[{"name":"Shanghai 411 Hospital, China RongTong Medical Healthcare Group Co. 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