Cuproptosis and Serine Metabolism Blockade Triggered by Copper‐Based Prussian Blue Nanomedicine for Enhanced Tumor Therapy

Cuproptosis, a newly defined cell death process, represents a novel modality with significant therapeutic potential in cancer treatment. Nevertheless, the modest concentration and transient half-life of copper ions in the bloodstream constrain their efficient delivery into tumor cells. In this study, a copper-based prussian blue nanostructure loaded with serine metabolic inhibitor (NCT-503@Cu-HMPB) is constructed for selectively inducing cuproptosis combined with disrupting serine metabolism. Released within the tumor cells, NCT-503 is found to inhibit cellular serine metabolism and GSH production, ultimately causing metabolic dysfunction, redox imbalance, and increased the formation of Cu⁺ that disrupts mitochondrial respiration chain, inducing lipoylated protein dihydrolipoamide S-acetyltransferase (DLAT) aggregation and consequential iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately results in cell death. The findings provide a novel paradigm for tumor therapy based on cuproptosis and metabolic reprogramming, offering prospects for the development of innovative nanotherapeutic platforms in the future.