No abstract

The efficient delivery of a therapeutic gene into target tissues has remained a major obstacle in realizing a viable gene-based medicine. Herein, we introduce a facile and universal strategy to construct a DNA nanostructure-based codelivery system containing a linear tumor therapeutic gene (p53) and a chemotherapeutic drug (doxorubicin, DOX) for combined therapy of multidrug resistant tumor (MCF-7R). This novel codelivery system, which is structurally similar to a kite, is rationally designed to contain multiple functional groups for the targeted delivery and controlled release of the therapeutic cargoes. The self-assembled DNA nanokite achieves efficient gene delivery and exhibits effective inhibition of tumor growth in vitro and in vivo without apparent systemic toxicity. These structurally and chemically well-defined codelivery nanovectors provide a new platform for the development of gene therapeutics for not only cancer but also a wide range of diseases.

In response to environmental variations, living cells need to arrange the conformational changes of macromolecules to achieve the specific biofunctions. Inspired by natural molecular machines, artificial macromolecular assemblies with controllable nanostructures and environmentally responsive functions can be designed. By assembling macromolecular nanostructures with noble metal nanoparticles, environmental information could be significantly amplified and modulated. However, manufacturing dynamic plasmonic nanostructures that are efficiently responsive to different stimuli is still a challenging task. Here we demonstrate a stimulus-responsive plasmonic nanosystem based on DNA origami-organized gold nanorods (GNRs). L-shaped GNR dimers were assembled on rhombus-shaped DNA origami templates. The geometry and chiral signals of the GNR nanoarchitectures respond to multiple stimuli, including glutathione reduction, restriction enzyme action, pH change, or photoirradiation. While the glutathione reduction or restriction enzyme caused irreversible changes in the plasmonic circular dichroism (CD) signals, both pH and light irradiation triggered reversible changes in the plasmonic CD. Our system transduces external stimuli into conformational changes and circular dichroism responses in near-infrared (NIR) wavelengths. By this approach, programmable optical reporters for essential biological signals can be fabricated.

Multidrug resistance (MDR) is am ajor obstacle in the clinical treatment of cancer.H erein, af acile strategy is reported to construct av ersatile DNAn anostructure as ac odelivery vector of RNAi nterference (RNAi)a nd chemodrugs to combat multidrug-resistant tumor (MCF-7R) in vitro and in vivo.I nt he tailored nanocarrier,t wo linear small hairpin RNA( shRNA) transcription templates targeting MDR-associated genes (gene of P-glycoprotein, at ypical drug efflux pump;a nd gene of survivin, ar epresentative anti-apoptotic protein) are precisely organized in the chemodrug (doxorubicin, DOX) pre-loaded DNAo rigami. With the incorporation of active targeting and controlled-release elements,t hese multifunctional DNAn anocarriers can successfully enter the target MCF-7R cells and synergistically inhibit tumor growth without apparent systemic toxicity.T his tailored DNAn anoplatform, whichc ombines RNAi therapya nd chemotherapy, provides anew strategy for the treatment of multidrug-resistant tumors.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

nanostructures ranging from 50 to 400 nm, which are optimal for drug delivery to tumor regions that exhibit the enhanced permeability and retention (EPR) effect associated with malignant growth. [7] The entire addressable origami nanostructure can serve as a drawing board, localizing multiple desired functional moieties (such as therapeutic cargoes and tumor targeting ligands) with rationally designed numbers and patterns. DNA-origami structures can be 3D containers with docking sites on the inner sides or in the cavities, protecting the assembled molecular cargoes from being interfered with by the external environment. Furthermore, dynamic origami with stimuli-triggered reconfiguration can be constructed, enabling a controllable therapeutic release to exert the desired functions at the desired sites. The subsequent sections will focus on the recent efforts to enhance the stability of DNA-origami nanostructures [8] and to employ them as drug-delivery vehicles both in vitro [9] and in vivo [10] (Figure 1). Stability of DNA-Origami VehiclesFor nanocarriers aimed at in vitro and in vivo drug delivery, the structural integrity when exposed to the cell medium and bodily fluids is an important feature. Yan and co-workers and Ding and co-workers have investigated the stability of naked DNA-origami nanostructures in cell lysates [8a] and live cells, respectively. [8b] Their results demonstrate that the DNA origami was stable in cell lysates for 12 h and slowly digested by live cells during a 72 h incubation. To neutralize the negative surface charges and to further improve the structural stability of the DNA nanostructures, Kostiainen and co-workers coated DNA-origami nanostructures with cowpea chlorotic mottle virus capsid protein [8c] or protein-dendron conjugates [8d] for enhancing the stability against endonucleases. For further increasing the stability of DNA nanostructures in vivo, Shih and co-workers enveloped DNA-origami octahedrons with a PEGylated lipid bilayer. [8e] Wrapped tightly by the surfactant-lipid bilayer, the DNA-origami nanostructures showed improved resistance to nuclease digestion in vitro and prolonged circulation half-life in mice. However, the protective lipid shells were too thick to permit the maintenance of the well-defined shapes of the encapsulated DNA-origami structures and the control over the ligand positioning. Schmidt and co-workers recently described a protection strategy for DNA origami using a cationic poly(ethylene glycol)-polylysine (PEG-PLys) block copolymer that binds The recent decades have seen a surge of new nanomaterials designed for efficient drug delivery. DNA nanotechnology has been developed to construct sophisticated 3D nanostructures and artificial molecular devices that can be operated at the nanoscale, giving rise to a variety of programmable functions and fascinating applications. In particular, DNA-origami nanostructures feature rationally designed geometries and precise spatial addressability, as well as marked biocompatibility, thus providing a promisin...