In the present study, the design, construction, and operation of a functional DNA-decorated dynamic gold (Au) nanomachine as a therapeutic agent for triple combinatorial anti-cancer therapy are revealed. Taking advantage of the intrinsic optical properties of Au nanoparticles, which depend on their size, a cytosine rich i-motif sequence is employed for intracellular pH-sensitive duplex dissociation and subsequent aggregation of the DNA-Au nanomachine, enabling anticancer drug release and photothermal ablation upon irradiation with infrared light. Moreover, another functional DNA sequence, a G-quadruplex, is exploited for the stable loading and intracellular delivery of a photosensitizer to achieve effective photodynamic therapy under red light illumination. The G-quadruplex-assisted enhanced reactive oxygen species generation, pH-responsive dynamic aggregation behavior, consequent drug release, and the photothermal effect are investigated. Furthermore, the combinatorial chemo, photodynamic, and photothermal therapeutic effects of the functional DNA-decorated Au nanomachines are evaluated in vitro and in vivo using a triple negative breast cancer model.

Incorporation of a desired stimuli-responsive unit in a stereospecific manner at the specific location within a nonlinear block copolymer architecture is a challenging task in synthetic polymer chemistry. Herein, we report a facile and versatile method to synthesize AB miktoarm block copolymers bearing a singlet oxygen (O)-labile regio and stereospecific β-aminoacrylate linkage with 100% E-configuration at the junction via a combination of amino-yne click chemistry and ring opening polymerization. Using this strategy, a series of O-responsive AB amphiphilic miktoarm (MA) copolymers composed of hydrophilic polyethylene glycol (PEG) as the A constituent and hydrophobic polycaprolactone (PCL) as the B constituent (MA-PEG- b-PCL) was synthesized by varying the block length of PCL. The self-assembly characteristics of these well-defined MA-PEG- b-PCL copolymers in an aqueous condition were studied by solvent displacement and thin-film hydration method, and their morphologies were investigated using transmission electron microscopy. The copolymers formed spherical, cylindrical, or lamella morphologies, depending on the chain length and preparation conditions. A hydrophobic photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX) were efficiently encapsulated into the hydrophobic core of MA-PEG- b-PCL copolymer micelles. These coloaded micelles were taken up by human breast cancer (MDA-MB-231) cells. Upon red laser light irradiation, the O-generated by the Ce6 induced photocleavage of the β-aminoacrylate moiety, leading to the dissociation of the micellar structure and triggered intracellular drug release for effective therapy. Overall, rapid disassembly upon O generation and subsequent controlled intracellular drug release suggested that these micelles bearing β-aminoacrylate linkage have a huge potential for on-demand drug delivery.

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The discovery of sequence-specific hybridization has allowed the development of DNA nanotechnology, which is divided into two categories: 1) structural DNA nanotechnology, which utilizes DNA as a biopolymer; and 2) dynamic DNA nanotechnology, which focuses on the catalytic reactions or displacement of DNA structures. Recently, numerous attempts have been made to combine DNA nanotechnologies with functional DNAs such as aptamers, DNAzymes, amplified DNA, polymer-conjugated DNA, and DNA loaded on functional nanoparticles for various applications; thus, the new interdisciplinary research field of "functional DNA nanotechnology" is initiated. In particular, a fine-tuned nanostructure composed of functional DNAs has shown immense potential as a programmable nanomachine by controlling DNA dynamics triggered by specific environments. Moreover, the programmability and predictability of functional DNA have enabled the use of DNA nanostructures as nanomedicines for various biomedical applications, such as cargo delivery and molecular drugs via stimuli-mediated dynamic structural changes of functional DNAs. Here, the concepts and recent case studies of functional DNA nanotechnology and nanostructures in nanomedicine are reviewed, and future prospects of functional DNA for nanomedicine are indicated.

The tumor microenvironment (TME), which is composed of cancer cells, stromal cells, immune cells, and extracellular matrices, plays an important role in tumor growth and progression. Thus, targeting the TME using a well‐designed nano‐drug delivery system is emerging as a promising strategy for the treatment of solid tumors. Compared to normal tissues, the TME presents several distinguishable physiological features such as mildly acidic pH, hypoxia, high level of reactive oxygen species, and overexpression of specific enzymes, that are exploited as stimuli to induce specific changes in the nanocarrier structures, and thereby facilitates target‐specific delivery of imaging or chemotherapeutic agents for the early diagnosis or effective treatment, respectively. Recently, smart nanocarriers that respond to more than one stimulus in the TME have also been designed to elicit a more desirable spatiotemporally controlled drug release. This review highlights the recent progress in TME‐sensitive nanocarriers designed for more efficient tumor therapy and imaging. In particular, the design strategies, challenges, and critical considerations involved in the fabrication of TME‐sensitive nanocarriers, along with their in vitro and in vivo evaluations are discussed.

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In article https://doi.org/10.1002/adfm.201705416, Won Jong Kim and co‐workers report a functional DNA‐decorated dynamic Au nanomachine for triple combinatorial anticancer therapy. Two functional DNA moieties, a cytosine rich i‐motif and a guanine rich G‐quadruplex, facilitate loading of a chemotherapeutic drug and a photosensitizer on the Au nanomachine, and subsequently exhibit a therapeutic effect. Moreover, the pH‐responsive aggregation of the Au nanomachines induces a photothermal effect.