Composite nano copper carrier combining cuproptosis and photodynamic therapy for spatiotemporal synergistic anti-tumor therapy.

Cuproptosis is a copper-dependent programmed cell death triggered by mitochondrial dysfunction, which offers significant anti-tumor potential but requires tumor-specific copper delivery to avoid systemic toxicity. Here, we developed a synergistic nanoplatform (Cu2O@SiO2-Ce6, CSC) integrating cuproptosis induction with photodynamic therapy (PDT). A cuprous oxide (Cu2O) core was encapsulated in silicon dioxide and covalently linked to the photosensitizer Ce6. After accumulating in tumor regions via the EPR effect, CSC releases a surge of copper ions upon encountering the acidic tumor microenvironment and lysosomes. These ions induce mitochondrial cuproptosis by aggregating lipoylated TCA cycle proteins and depleting Fe-S cluster proteins. Concurrently, laser irradiation activates Ce6 to generate cytotoxic reactive oxygen species, actively disrupting tumor membranes. The experiments showed that the nanoplatform significantly enhanced the tumor cell killing effect and reduced the toxicity to normal tissues through a dual mechanism, which provided a new strategy for overcoming the drug resistance of PDT and the precise regulation of cuproptosis.