Abstract The latest research identifies that cysteine (Cys) is one of the key factors in tumor proliferation, metastasis, and recurrence. The direct depletion of intracellular Cys shows a profound antitumor effect. However, using nanozymes to efficiently deplete Cys for tumor therapy has not yet attracted widespread attention. Here, a (3‐carboxypropyl) triphenylphosphonium bromide‐derived hyaluronic acid‐modified copper oxide nanorods (denoted as MitCuOHA) are designed with cysteine oxidase‐like, glutathione oxidase‐like and peroxidase‐like activities to realize Cys depletion and further induce cellular ferroptosis and cuproptosis for synergistic tumor therapy. MitCuOHA nanozymes can efficiently catalyze the depletion of Cys and glutathione (GSH), accompanied by the generation of H 2 O 2 and the subsequent conversion into highly active hydroxyl radicals, thereby successfully inducing ferroptosis in cancer cells. Meanwhile, copper ions released by MitCuOHA under tumor microenvironment stimulation directly bind to lipoylated proteins of the tricarboxylic acid cycle, leading to the abnormal aggregation of lipoylated proteins and subsequent loss of iron–sulfur cluster proteins, which ultimately triggers proteotoxic stress and cell cuproptosis. Both in vitro and in vivo results show the drastically enhanced anticancer efficacy of Cys oxidation catalyzed by the MitCuOHA nanozymes, demonstrating the high feasibility of such catalytic Cys depletion‐induced synergistic ferroptosis and cuproptosis therapeutic concept.
