A degradable multi-metal-chelating stealth nanoplatform for dual ferroptosis/cuproptosis-enhanced metalloimmunotherapy in leukemia

Abstract Acute myeloid leukemia (AML) remains a challenging hematologic malignancy with limited treatment options and poor prognosis. Here, we report the development of a multifunctional, pH-responsive, and biodegradable nanoparticle system, Membrane/Cu-HMPB@DSF/RSL3, for synergistic AML therapy. Constructed upon the Prussian blue-based frameworks and cloaked with leukemia cell membranes, these nanoparticles preferentially accumulate in AML cells and release copper, iron, and manganese ions, along with disulfiram (DSF) and RSL3, under mildly acidic intracellular conditions. The released metal ions catalyze Fenton-like reactions, deplete intracellular glutathione (GSH), and induce ferroptosis and cuproptosis in cooperation with the loaded small-molecule drugs. Meanwhile, manganese ions activate the cGAS-STING pathway, triggering innate immune responses and promoting immune cell recruitment. Both in vitro and in vivo studies demonstrated robust anti-AML efficacy with minimal systemic toxicity. This work presents a modular and immunogenic nanoplatform that holds broad potential for AML treatment and beyond. Graphical abstract