Mild‐Photothermal Effect Induced High Efficiency Ferroptosis‐Boosted‐Cuproptosis Based on Cu₂O@Mn₃Cu₃O₈ Nanozyme

Abstract

A core‐shell‐structured Cu2O@Mn3Cu3O8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)‐activated copper ionophore to achieve safe and efficient cuproptosis. The Mn3Cu3O8 shell not only prevents exposure of normal tissues to the Cu2O core to reduce systemic toxicity but also exhibits enhanced enzyme‐mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)‐like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)‐like activity catalyzes the overexpressed H2O2 in the TME, thereby generating O2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton‐like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress‐induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme‐mimicking activity. The mild photothermal effect enhances the enzyme‐mimicking activity of the CMCO nanozymes, thus inducing high‐efficiency ferroptosis‐boosted‐cuproptosis.

Advances in H2O2-supplying materials for tumor therapy: synthesis, classification, mechanisms, and applications

“…In addition to promoting H 2 O 2 production, these materials exhibited multiple antitumor mechanisms such as starvation therapy, 129 calcium overloading, 164 ferroptosis, 165 and cuproptosis. 166…”

Coordination Self-Assembled AuTPyP-Cu Metal–Organic Framework Nanosheets with pH/Ultrasound Dual-Responsiveness for Synergistically Triggering Cuproptosis-Augmented Chemotherapy

“…This cascade of events results in cell membrane ruptures, endoplasmic reticulum damage, impaired mitochondrial function, and ultimately cell death. The interplay of these processes is modulated by FDX1 and lipoic acid synthase (LIAS). , Moreover, the depletion of intracellular glutathione (GSH) by CDT results in increased cell sensitivity to the stimuli from oxidative stress or chemotherapy drugs, together causing prominent cell death . The mitochondrion is known to yield approximately 90% of cellular ROS, which is a main site of cuproptosis, in which massive ROS generated and induced the following lipid peroxidation and DNA damage .…”

Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia

“…However, excessive accumulation of copper in cells can lead to oxidative stress and disrupt normal cellular functions. Therefore, the maintenance of copper homeostasis is tightly regulated. − In 2022, Golub’s team introduced the concept of “cuproptosis” as a novel form of regulated cell death that has since gained significant attention in the context of tumor suppression . In cuproptosis, excess copper binds to esteroylated components in the tricarboxylic acid (TCA) cycle within mitochondria, inducing protein toxic stress that ultimately leads to cell death. − Unlike traditional therapies, cuproptosis offers advantages by circumventing issues related to drug resistance. − However, its therapeutic efficacy has certain limitations.…”