Ferritin-mediated copper delivery induces dual cell death across diverse leukemia types.

Durable treatment of leukemia remains challenging because most therapeutic regimens rely on a single cytotoxic mechanism. Here, we report a rationally loaded cuprous oxide ferritin nanoplatform (Cu2O@Fn) that enables targeted induction of dual cell death in leukemia. By exploiting the intrinsic binding of ferritin to CD71, which is broadly expressed across leukemia types, Cu2O@Fn achieves efficient and selective intracellular delivery in diverse leukemia cell lines and patient-derived bone marrow samples. Upon cellular uptake, the controlled release of copper ions engages dual death pathways: Cu+ mediated Fenton-like reactions drive ferroptosis, and subsequent Cu2+ overload triggers cuproptosis, collectively resulting in irreversible mitochondrial damage. Comprehensive evaluation across multiple in vitro systems, cell-line-derived xenografts, and a CD71-humanized leukemia model demonstrates robust and broad-spectrum anti-leukemic efficacy, including performance exceeding established clinical treatment regimens. Together, this work establishes ferritin-mediated copper delivery as a neotype therapeutic strategy against leukemia.