Nanotrains of DNA Copper Nanoclusters That Triggered a Cascade Fenton-Like Reaction and Glutathione Depletion to Doubly Enhance Chemodynamic Therapy

Many current chemodynamic therapy (CDT) strategies suffer from either low therapeutic efficiency or the deficiency of poor targeting. The low therapeutic efficiency is mainly ascribed to the intracellular antioxidant system and the inefficient Fenton reaction in the weakly acidic tumor microenvironment (TME). Herein, by exploitation of the diverse function and programmability of functional nucleic acid, aptamer-tethered nanotrains of DNA copper nanoclusters (aptNTDNA-CuNCs) were assembled to simultaneously achieve targeted recognition, loading, and delivery of CDT reagents into tumor cells without an external carrier. The intracellular hydrogen peroxide (H2O2) oxidized nanotrains of DNA-CuNCs to produce a lot of Cu2+ and Cu+ ions, which can generate reactive oxygen species (ROS) in the weakly acidic TME based on the pH-independent Fenton-like reaction of Cu+/H2O2. Meanwhile, the redox reaction between intracellular glutathione (GSH) and Cu2+ depleted GSH and generated Cu+ ions, which weakened the antioxidant ability of cancer cells and further enhanced the Fenton-like reaction of Cu+/H2O2, respectively. Thus, the cascade Fenton-like reaction and GSH depletion doubly improved the efficacy of CDT. The in vivo and in vitro study solidly confirmed that aptNTDNA-CuNCs have excellent antitumor efficacy and no cytotoxicity to healthy cells. Therefore, aptNTDNA-CuNCs can act as CDT reagents to achieve highly efficient, biocompatible, and targeted CDT.