Copper peroxide and cisplatin co-loaded silica nanoparticles-based trinity strategy for cooperative cuproptosis/chemo/chemodynamic cancer therapy

Cuproptosis, a novel identified regulated cell death modality, makes a great difference to known death mechanisms and offers encouraging opportunities for copper-based materials for cancer treatment. However, its capacity for killing cancer cells is restricted by the lack of tumor selectivity. Tumor microenvironment, characterized by hypoxia, acidosis and excessive glutathione (GSH), is another limitation of cuproptosis and cisplatin-based chemotherapy. Herein, a newly copper/cisplatin hybrid silica nanoplatform, denoted as CuO2/ DDP@SiO2, is developed as copper metabolic disrupter and chemotherapy/chemodynamic therapy amplifier for synergistic cuproptosis/chemo/chemodynamic anticancer therapy. We imbued CuO2 with the rever-TME properties: O2 generation, increased pH value and oxidation of intracellular GSH. The depletion of GSH sensitizes cancer cells to the CuO2/DDP@SiO2-mediated cuproptosis, causing aggregation of lipoylated mitochondrial proteins, the target of copper-induced toxicity. In vitro experiments shown that reduced binding of GSH to cisplatin could largely increase intracellular cisplatin concentration. Simultaneously, CuO2 could significantly downregulate multidrug resistance-associated protein 2 (MRP2) by O2-dependent hypoxia-inducible factor 1 (HIF-1) inactivation. Thus, the entire cisplatin-efflux pathway was blocked, and the antitumor effect of cisplatin was enhanced both in vitro and in vivo. Collectively, both chemotherapy/chemodynamic therapy and cuproptosis were enhanced by TME modulation. Therefore, CuO2/DDP@SiO2 nanoparticle provides a new therapeutic modality paradigm to boost cuproptosis/chemo/chemodynamic therapies.