Bioinspired Ultrastable Cu(I)-Bovine Serum Albumin Single-Atom Nanozymes Enable MRI-Trackable Synergistic Catalytic Therapy and Cuproptosis for Tumors

Monovalent copper (Cu(I)) drives cuproptosis and catalytic therapy, yet its rapid oxidation reduces the activity. We developed bioinspired Cu(I)-bovine serum albumin single-atom nanozymes (Cu(I)-BSA SAzymes) via mild biomineralization, achieving stability (>90 days) and dual enzyme-like activities (peroxidase (POD)/catalase (CAT)) to convert tumor H₂O₂ into cytotoxic reactive oxygen species (ROS) while alleviating hypoxia. These SAzymes deplete glutathione to amplify oxidative stress and release Cu(I), which aggregates dihydrolipoamide S-acetyltransferase (DLAT) to induce cuproptosis─distinct from apoptosis/ferroptosis. Mechanistically, transcriptomics analyses suggest that Cu(I)-BSA SAzymes exerted their effects by regulating the oxidative stress and energy metabolism in 4T1 cells. The tumor microenvironment further mediates SAzymes aggregation and in situ transformation into paramagnetic Cu(II), enabling self-amplified T₁-weighted MRI contrast for real-time activation monitoring. In breast (4T1) and colon (CT26) tumors, Cu(I)-BSA SAzymes suppress growth by 68.8% and 80.3% ([Cu] = 4 mg kg^-1). This study reports a stable Cu(I) platform for catalytic-plus-cuproptosis theranostics.