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

Abstract 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.