Biomimetic Copper-Doped Nano-Aluminum Adjuvant Potentiates Therapy in Chemoresistant Acute Myeloid Leukemia
- Adv Healthc Mater. 2026 May;15(19):e04039. doi: 10.1002/adhm.202504039.
- 1. Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, P. R. China.
- 2. Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.
- 3. Department of Pharmacy, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, P. R. China.
- 4. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, P. R. China.
- 5. The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
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.