Lipid Droplet‐Targeted Biomimetic Liposomes Potentiate Chemo‐Ferroptosis Therapy in Leukemia

Chemotherapy remains the primary treatment modality for leukemia, yet relapse frequently occurs due to the persistence of chemoresistant leukemia cells (LCs) within the bone marrow (BM). Ferroptosis-based therapies provide a promising strategy for eliminating these resistant cells. Here, we demonstrate that cytarabine chemotherapy promotes lipid droplet (LD) accumulation in BM-resident LCs, thereby conferring resistance to ferroptosis. Based on these findings, we developed a biomimetic liposome (REM@HLipo) co-encapsulating RSL3 (a ferroptosis inducer), elacytarabine (a cytarabine prodrug), and metformin (an LD disruptor) to enhance chemo-ferroptosis therapy against leukemia. Upon targeted delivery to BM-resident LCs, metformin disrupts LDs and increases the availability of polyunsaturated fatty acids (PUFAs) for oxidation, thereby sensitizing LCs to RSL3-induced ferroptosis. This effect synergizes with cytarabine to exert potent cytotoxicity against BM-resident 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-ferroptosis therapeutic regimen for leukemia management.