DNA Logic Circuit-Equipped Redox Imbalance Amplifier for Precise Mitochondrial Disruption and Efficient Cancer...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Mitochondrial function modulation is a promising cancer therapy strategy.
• Existing therapies face challenges in precise targeting and efficacy.

Purpose of the Study:

• To develop a DNA logic circuit-equipped redox imbalance amplifier for precise cancer cell mitochondrial disruption.
• To enhance cancer therapy through targeted induction of ferroptosis and cuproptosis.

Main Methods:

• Constructed a nanoamplifier using metal phenolic networks, metal-organic frameworks, vitamin K3, and DNA logic circuits.
• Utilized tumor microenvironment cues and survivin mRNA as AND gate inputs for DNA logic circuit activation.
• Engineered the nanoamplifier to disrupt mitochondrial membrane potential, generate reactive oxygen species (ROS), deplete glutathione, and induce lipid peroxidation.

Main Results:

• The nanoamplifier successfully disintegrated in the tumor microenvironment, releasing active components.
• DNA logic circuits formed aggregates on mitochondria, triggering ROS generation and mitochondrial dysfunction.
• Achieved synergistic cancer cell death via ferroptosis and cuproptosis, enhanced by vitamin K3-mediated ROS amplification.

Conclusions:

• The developed smart nanoamplifier offers a precise and effective strategy for disrupting mitochondrial redox homeostasis in cancer cells.
• This approach presents a novel paradigm for cancer therapy by integrating multiple cell death pathways.
• The study highlights the potential of logic-gated nanomedicine for advanced therapeutic applications.