Engineering cuproptosis with nanomedicine: Design, combination therapy, and translation in cancer

Cuproptosis is a distinct form of regulated cell death triggered by copper and characterized by the aggregation of lipoylated mitochondrial proteins, destabilization of iron-sulfur cluster proteins, and proteotoxic stress. Unlike nonspecific copper toxicity, cuproptosis depends on a defined biochemical context shaped by FDX1-associated protein lipoylation, oxidative carbon metabolism, and mitochondrial substrate competence. These features may create a therapeutic vulnerability in tumors with high oxidative phosphorylation, but they also impose substantial translational challenges. Free copper ions and conventional copper ionophores often lack the tumor selectivity, pharmacological control, and safety required for systemic use, and copper exposure alone is insufficient unless it can be converted into sustained mitochondrial stress in susceptible tumor cells. Nanomedicine can provide spatiotemporal and chemical control over tumor copper stress. By enabling tumor-selective accumulation, stimulus-responsive activation, mitochondrial targeting, and modulation of copper homeostasis, nanoplatforms may help convert cuproptosis from a biochemical phenomenon into a therapeutically tractable strategy. These capabilities create opportunities to integrate cuproptosis with broader tumor vulnerabilities, including redox imbalance, metabolic plasticity, and altered immune states. This Review examines the molecular basis of cuproptosis and tumor susceptibility, the design and combination strategies of cuproptosis-oriented nanomedicines, and the translational challenges that must be addressed to move the field beyond proof of concept. Future advances are likely to depend on precise control of copper bioavailability and mitochondrial targeting, together with biomarker-guided patient selection and clinically tractable platform design.