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

Precision modulation of mitochondrial function has emerged as a novel strategy in the field of cancer therapy. Herein, we proposed a DNA logic circuit-equipped redox imbalance amplifier that can enable precise mitochondrial disruption and efficient cancer therapy. This proposed redox imbalance amplifier consisting of metal phenolic-network (MPN)-coated metal-organic framework, hydrogen peroxide (H2O2)-supplier vitamin k3 (Vk3), and DNA logic circuit. The protective MPN shell of this nanoamplifier can be specifically disintegrated by tumor microenvironments to release Cu2+, Fe3+, and Vk3 and cyanine dye-modified-DNA logic circuit. The abnormally tumor microenvironment and survivin mRNA were chosen as "AND" gate inputs of DNA logic circuit. The released DNA logic circuit response to these inputs can form DNA aggregates on the mitochondria, thus resulting in a cascade of mitochondrial membrane potential disruption and promoting reactive oxygen species (ROS) generation. Furthermore, the subsequent Cu2+/Fe3+-mediated glutathione depletion and massive ROS production can exacerbate oxidative stress and accumulation of toxic lipid peroxides, finally triggering ferroptosis. Concurrently, the cuproptosis was promoted through copper ion-mediated aggregation of dihydrolipoamide S-acetyltransferase. Given that H2O2 levels within tumor cells are insufficient to effectively generate ROS, the released Vk3 can serve as H2O2 supplier and thereby further elevate oxidative stress levels. This strategy integrates multiple elements and AND logic gates into a single smart nanoamplifier for precise and boost disruption of mitochondrial redox homeostasis in tumor cells. We believe this work will provide a smart and effective paradigm for tumor therapy.