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Hyeongmok Park1 2 Jinhwan Kim2 Sungjin Jung2 3 Won Jong Kim1 2 3

1, Pohang University of Science and Technology (POSTECH), Pohang, , Korea (the Republic of)
2, Institute for Basic Science (IBS), Pohang, , Korea (the Republic of)
3, Pohang University of Science and Technology (POSTECH), Pohang, , Korea (the Republic of)

The construction of artificial complex materials, incorporating biomolecules that respond to biological circumstances in a smart manner, is a big challenge in nano-biomedical research. As a component of complex materials, DNA has attracted researchers because of its advantages, such as programmability, predictability, and biocompatibility. Specific DNA sequences can alter their conformation depending on specific environments, therefore, DNA sequences have been utilized as a trigger for the dynamic structural changes of nanomachine. Moreover, various biomolecules and chemical drugs are easily incorporated via specific DNA hybridization, therefore, DNA-based nanomachines have also shown immense potential as a drug delivery vehicle. However, DNA alone is not sufficient for use as a biological nanomachine because of its lack of functionality; consequently, a hybrid system composed of DNA and other functional materials should be developed. Among various DNA-based hybrid systems, the gold nanoparticle-DNA (AuNP-DNA) hybrid system is widely used for biomedical applications because of the advantages including biocompatibility and plasmonic properties.
The development of a multi-functional nanomachine as a combinatorial therapeutic agent for the treatment of specific disease is a research goal in this study. Especially, the use of combinatorial therapeutic agents in anti-cancer therapy is considered a promising approach, as the complete treatment of cancer cannot be achieved using a single agent because of the intrinsic complexity of cancer. Among various therapeutic combinations, phototherapy with chemotherapy, is regarded as a potent combination for efficient anti-cancer therapy. Therefore, a combinatorial therapeutic agent which induces an appropriate photothermal and photodynamic effect, combined with chemotherapeutic effect is highly demanded to maximize the anti-cancer therapeutic effect.
Herein, we reveal the design, construction, and operation of a functional DNA-decorated dynamic Au nanomachine as a therapeutic agent for triple combinatorial anti-cancer therapy. Taking advantage of the intrinsic optical properties of Au nanoparticles, which depend on their size, a cytosine rich i-motif sequence was employed for intracellular pH-sensitive duplex dissociation and subsequent aggregation of the DNA-Au nanomachine, enabling anticancer drug release and photothermal ablation upon infrared light irradiation. Moreover, another functional DNA sequence, a G-quadruplex, was exploited for the stable loading and intracellular delivery of a photosensitizer to achieve effective photodynamic therapy under red light illumination. The therapeutic properties and dynamics of DNA-Au nanomachine were investigated. Furthermore, the combinatorial chemo, photodynamic, and photothermal therapeutic effects of the functional DNA-decorated Au nanomachines were evaluated in vitro and in vivo using a triple negative breast cancer model.

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