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.
[1]Shanghai Univ, Shanghai Hosp 411, China RongTong Med Healthcare Grp Co Ltd Hosp 411, Hosp 411, Shanghai, Peoples R China.
[2]Shanghai Univ, Inst Artificial Intelligence & Biomfg, Shanghai, Peoples R China.
[3]Natl Univ Singapore, Dept Chem, Singapore, Singapore.
[4]Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Sch Med, Shanghai, Peoples R China.
[5]Shanghai Jiao Tong Univ, State Key Lab Syst Med Canc, Sch Med, Shanghai, Peoples R China.
(8.0+极速模式)