Biomimetic Copper-Doped Nano-Aluminum Adjuvant Potentiates Therapy in Chemoresistant Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy with frequent resistance to first-line cytarabine-based chemotherapy, primarily driven by heightened mitochondrial function. Here, we develop a copper-doped nano-aluminum adjuvant (CuNA) to overcome this resistance by targeting mitochondrial vulnerability. Upon internalization, CuNA releases Cu² ⁺, leading to intracellular Cu²⁺ overload, which disrupts mitochondrial function and induces ferroptosis in drug-resistant AML cells, thereby markedly enhancing cytarabine sensitivity. Moreover, CuNA downregulates cholesterol biosynthesis and antioxidant defense pathways, including suppression of HMG-CoA reductase and glutathione peroxidase 4, further amplifying ferroptosis in combination with cytarabine. In drug-resistant AML mouse models, CuNA coated with AML cell membranes demonstrates efficient tumor targeting, robust suppression of leukemia progression, and prolonged survival. This study highlights CuNA as a promising tool to overcome chemoresistance mediated by mitochondrial reprogramming in AML.