Regenerating Chemotherapeutics through Copper‐Based Nanomedicine: Disrupting Protein Homeostasis for Enhanced Tumor Therapy

Abstract The bis‐(diethyldithiocarbamate)‐copper (CuET), the disulfiram (DSF)‐Cu complex, has exhibited noteworthy anti‐tumor property. However, its efficacy is compromised due to the inadequate oxidative conditions and the limitation of bioavailable copper. Because CuET can inactivate valosin‐containing protein (VCP), a bioinformatic pan‐cancer analysis of VCP is first conducted in this study to identify CuET as a promising anticancer drug for diverse cancer types. Then, based on the drug action mechanism, a nanocomposite of CuET and copper oxide (CuO) is designed and fabricated utilizing bovine serum albumin (BSA) as the template (denoted as CuET‐CuO@BSA, CCB). CCB manifests peroxidase (POD)‐mimicking activity to oxidize the tumor endogenous H 2 O 2 to generate reactive oxygen species (ROS), enhancing the chemotherapy effect of CuET. Furthermore, the cupric ions released after enzymatic reaction can regenerate CuET, which markedly perturbs intracellular protein homeostasis and induces apoptosis of tumor cells. Meanwhile, CCB triggers cuproptosis by inducing the aggregation of lipoylated proteins. The multifaceted action of CCB effectively inhibits tumor progression. Therefore, this study presents an innovative CuET therapeutic strategy that creates an oxidative microenvironment in situ and simultaneously self‐supply copper source for CuET regeneration through the combination of CuO nanozyme with CuET, which holds promise for application of CuET for effective tumor therapy.