Nucleolin-Targeted DNA Nanoflowers Enable Multimodal Synergistic Cancer Therapy

Copper plays multifunctional roles in both physical processes and cancer development. Since copper is an excellent candidate for Fenton-like reactions and the inducer of cuproptosis, copper-based antitumor drugs have attracted many researchers in recent years. However, there are still some barriers to their clinical application, such as leakage to normal tissues, excess of glutathione (GSH), and lack of H₂O₂ in the tumor microenvironment, indicating that copper alone is not enough for cancer therapy. Herein, we constructed a DNA-based nanodrug loaded with Cu²⁺ and glucose oxidase (GOx) for synergistic cancer therapy, namely, glucose oxidase-copper-DNA hybrid nanoflower (GCD). AS1411 aptamer, coded in the long single-stranded DNA sequence, provided GCD with tumor-targeting ability, enhancing its bio-safety. The addition of GOx not only provided adequate H₂O₂ but also helped deplete GSH. Besides, as it oxidated glucose to gluconic acid, the main energy source of tumor cells was cut off. The in vitro and in vivo antitumor ability of GCD was verified. We also examined immune cell death induction and the immune regulation role of GCD and found that the combination of anti-programmed death-1 antibody further enhanced its antitumor effect. These results contribute to the further study and application of copper-based drug development.