Engineering Urchin‐Shaped Copper Nanospheres for Synergistic Apoptosis and Cuproptosis via Oxidative Stress Amplification in Cancer Therapy

ABSTRACT The clinical application of conventional chemotherapy is significantly limited by severe toxic side effects, creating an urgent demand for the development of high‐performance nanomedicines that can enhance therapeutic efficacy while minimizing adverse reactions. Herein, we develop artemisinin‐loaded urchin‐shaped copper nanospheres (ART@HCuMSN) for synergistic induction of apoptosis and cuproptosis via oxidative stress amplification in cancer therapy. ART@HCuMSN exhibit tumor microenvironment‐activated catalytic activity, wherein released Cu 2+ catalyzes the conversion of exogenous artemisinin (ART) and endogenous hydrogen peroxide (H 2 O 2 ) into carbon‐centered radicals (·C) and hydroxyl radicals (·OH), and depletes intracellular glutathione (GSH), thereby exacerbating oxidative stress in tumor cells and inducing apoptosis. Furthermore, the enhanced oxidative stress heightens the susceptibility of cancer cells to copper, triggering pronounced proteotoxic stress, which subsequently activates the cellular cuproptosis pathway. Evidence from both in vitro and in vivo studies provides compelling support for the potent antitumor efficacy and excellent biosafety of these sea urchin‐shaped copper nanospheres. This study establishes a crucial foundation for developing in situ apoptosis/cuproptosis synergistic therapeutic strategies based on copper‐based nanospheres.