NQO1‑activated self‑reinforcing bimetallic nanoplatform triggers ferroptosis and cuproptosis for osteosarcoma therapy.

Abstract

Osteosarcoma, the most common primary malignant bone tumor in adolescents, has a poor prognosis due to high rates of metastasis, recurrence, and chemoresistance, necessitating novel treatments. Herein, a biomimetic nanoplatform CFCM/VK3 was engineered to exploit synergistic iron-copper interference against osteosarcoma. This platform comprises an optimized CuFe2O4 nanoparticle core with superior Fenton-like activity, glutathione depletion capacity, and near-infrared photothermal properties, combined with vitamin K3 (VK3) as an endogenous H2O2 generator specifically activated by tumor-overexpressed quinone oxidoreductase 1 (NQO1). The core is cloaked with K7M2 osteosarcoma cell membranes to enable homologous targeting and immune evasion. After tumor-specific uptake, the acidic microenvironment activates VK3 to generate H2O2 and liberates iron and copper ions. This initiates a self-reinforcing cascade wherein iron-driven oxidative stress impairs mitochondrial ATP synthesis, and the resultant energy shortage traps copper inside cells, thereby amplifying the toxicity of both ions. Critically, the cooperative action of iron and copper simultaneously activates two regulated cell death pathways: iron‑dependent lipid peroxidation leads to ferroptosis and copper‑induced aggregation of lipoylated proteins triggers cuproptosis. Near-infrared irradiation further accelerates these catalytic reactions and provides photothermal ablation. The CFCM/VK3 nanoplatform demonstrates significant tumor suppression and excellent biosafety in an osteosarcoma mouse model, establishing a new paradigm of metal-ion interference therapy that leverages the mutual dependency between iron and copper for self-amplifying antitumor effects.