DNAzyme-Mediated Cascade Nanoreactor for Cuproptosis-Promoted Pancreatic Cancer Synergistic Therapy

Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper-based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu⁺ can release from the nanosystem. Since Cu⁺ having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu⁺ induces cuproptosis and CDT efficiently, accompanied by Cu²⁺ generation. Then Cu²⁺ can be converted into Cu⁺ partially by glutathione (GSH) to from a Cu⁺ supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn²⁺ form DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis.