Nucleolin-Targeted DNA Nanoflowers Enable Multimodal Synergistic Cancer Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Copper ions are crucial in biological processes and cancer development, showing potential for Fenton-like reactions and inducing cuproptosis.
• Copper-based anticancer drugs face challenges like normal tissue leakage, high glutathione levels, and low hydrogen peroxide in tumors.
• Existing therapies highlight the need for advanced copper-based drug delivery systems to overcome tumor microenvironment limitations.

Purpose of the Study:

• To design and evaluate a DNA-based nanodrug (GCD) for synergistic cancer therapy using copper ions and glucose oxidase.
• To enhance the safety and efficacy of copper-based cancer treatment by addressing tumor microenvironment challenges.
• To investigate the potential of GCD in inducing immune cell death and its role in immune regulation for improved antitumor outcomes.

Main Methods:

• Construction of a DNA-based nanodrug (GCD) incorporating Cu2+ and glucose oxidase (GOx), functionalized with AS1411 aptamer for tumor targeting.
• In vitro and in vivo evaluation of the synergistic antitumor efficacy of GCD, assessing its ability to generate H2O2, deplete GSH, and inhibit tumor cell energy supply.
• Analysis of immune cell death induction and immune regulatory effects of GCD, including combination therapy with anti-programmed death-1 antibody.

Main Results:

• The developed GCD nanodrug demonstrated effective tumor targeting and enhanced bio-safety due to the AS1411 aptamer.
• GCD successfully generated sufficient H2O2, depleted tumor glutathione, and cut off glucose metabolism, leading to significant in vitro and in vivo antitumor activity.
• GCD induced immune cell death and exhibited immune regulatory properties, with combination therapy using anti-PD-1 antibody further boosting the antitumor effect.

Conclusions:

• The glucose oxidase-copper-DNA hybrid nanoflower (GCD) represents a promising strategy for synergistic cancer therapy by overcoming limitations of copper-based drugs.
• GCD effectively targets tumors, modulates the tumor microenvironment, and elicits an anti-tumor immune response.
• Further research into GCD and combination therapies holds potential for advancing copper-based drug development in oncology.