Nanomaterials for precise cuproptosis modulation: From molecular mechanisms to systemic therapeutics

Cuproptosis is a mitochondria centered, metabolism linked cell death in which the ferredoxin 1 and pyruvate dehydrogenase axis generates cuprous ion inside the matrix and installs lipoylated targets. Surplus cuprous ion binding drives protein aggregation, loss of iron-sulfur clusters, and dysfunction of mitochondria respiration. Many therapy resistant tumors shift toward oxidative phosphorylation and rewire copper homeostasis, creating a selective weakness to copper ionophores. Restoring these mitochondrial inputs may resensitize tumors and promote immunogenic control. Susceptibility is set by copper access, and metabolic state. Cuproptosis intersects with ferroptosis, pyroptosis, necroptosis, and disulfidptosis through shared thiol or redox nodes, placing glutathione as a central determinant and providing a mechanistic rationale for synergistic combinations. Mechanism-guided nanomedicines now pair copper delivery with mitochondrial targeting, glutathione (GSH) modulation, and metabolic-immune co-therapies, often using stimuli-triggered Cu(II) to Cu(I) conversion. Localizing active copper while limiting buffering can enhance lipoylated protein aggregation, reduce required dosing, and resensitize resistant tumors, with potential immune gains.