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      A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads

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      Science
      American Association for the Advancement of Science (AAAS)

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          Nanorobots Deliver

          DNA aptamers are short strands that have high binding affinity for a target protein that can be used as triggers for releasing cargo from delivery vehicles. Douglas et al. (p. [Related article:]831 ) used this strategy to design DNA origami “nanorobots”—complex shaped structures created by manipulating a long DNA strand through binding with shorter “staple” strands—that could deliver payloads such as gold nanoparticles or fluorescently labeled antibody fragments. These nanorobots were designed to open in response to specific cell-surface proteins, releasing molecules that triggered cell signaling.

          Abstract

          Cargoes stored in folded DNA origami are released when aptamers in the structure bind target protein molecules.

          Abstract

          We describe an autonomous DNA nanorobot capable of transporting molecular payloads to cells, sensing cell surface inputs for conditional, triggered activation, and reconfiguring its structure for payload delivery. The device can be loaded with a variety of materials in a highly organized fashion and is controlled by an aptamer-encoded logic gate, enabling it to respond to a wide array of cues. We implemented several different logical AND gates and demonstrate their efficacy in selective regulation of nanorobot function. As a proof of principle, nanorobots loaded with combinations of antibody fragments were used in two different types of cell-signaling stimulation in tissue culture. Our prototype could inspire new designs with different selectivities and biologically active payloads for cell-targeting tasks.

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          Most cited references23

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          Self-assembly of DNA into nanoscale three-dimensional shapes

          Molecular self-assembly offers a ‘bottom-up’ route to fabrication with subnanometre precision of complex structures from simple components1. DNA has proven a versatile building block2–5 for programmable construction of such objects, including two-dimensional crystals6, nanotubes7–11, and three-dimensional wireframe nanopolyhedra12–17. Templated self-assembly of DNA18 into custom two-dimensional shapes on the megadalton scale has been demonstrated previously with a multiple-kilobase ‘scaffold strand’ that is folded into a flat array of antiparallel helices by interactions with hundreds of oligonucleotide ‘staple strands’19, 20. Here we extend this method to building custom three-dimensional shapes formed as pleated layers of helices constrained to a honeycomb lattice. We demonstrate the design and assembly of nanostructures approximating six shapes — monolith, square nut, railed bridge, genie bottle, stacked cross, slotted cross — with precisely controlled dimensions ranging from 10 to 100 nm. We also show hierarchical assembly of structures such as homomultimeric linear tracks and of heterotrimeric wireframe icosahedra. Proper assembly requires week-long folding times and calibrated monovalent and divalent cation concentrations. We anticipate that our strategy for self-assembling custom three-dimensional shapes will provide a general route to the manufacture of sophisticated devices bearing features on the nanometer scale.
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            Folding DNA to create nanoscale shapes and patterns.

            'Bottom-up fabrication', which exploits the intrinsic properties of atoms and molecules to direct their self-organization, is widely used to make relatively simple nanostructures. A key goal for this approach is to create nanostructures of high complexity, matching that routinely achieved by 'top-down' methods. The self-assembly of DNA molecules provides an attractive route towards this goal. Here I describe a simple method for folding long, single-stranded DNA molecules into arbitrary two-dimensional shapes. The design for a desired shape is made by raster-filling the shape with a 7-kilobase single-stranded scaffold and by choosing over 200 short oligonucleotide 'staple strands' to hold the scaffold in place. Once synthesized and mixed, the staple and scaffold strands self-assemble in a single step. The resulting DNA structures are roughly 100 nm in diameter and approximate desired shapes such as squares, disks and five-pointed stars with a spatial resolution of 6 nm. Because each oligonucleotide can serve as a 6-nm pixel, the structures can be programmed to bear complex patterns such as words and images on their surfaces. Finally, individual DNA structures can be programmed to form larger assemblies, including extended periodic lattices and a hexamer of triangles (which constitutes a 30-megadalton molecular complex).
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              A DNA-fuelled molecular machine made of DNA.

              Molecular recognition between complementary strands of DNA allows construction on a nanometre length scale. For example, DNA tags may be used to organize the assembly of colloidal particles, and DNA templates can direct the growth of semiconductor nanocrystals and metal wires. As a structural material in its own right, DNA can be used to make ordered static arrays of tiles, linked rings and polyhedra. The construction of active devices is also possible--for example, a nanomechanical switch, whose conformation is changed by inducing a transition in the chirality of the DNA double helix. Melting of chemically modified DNA has been induced by optical absorption, and conformational changes caused by the binding of oligonucleotides or other small groups have been shown to change the enzymatic activity of ribozymes. Here we report the construction of a DNA machine in which the DNA is used not only as a structural material, but also as 'fuel'. The machine, made from three strands of DNA, has the form of a pair of tweezers. It may be closed and opened by addition of auxiliary strands of 'fuel' DNA; each cycle produces a duplex DNA waste product.
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                Author and article information

                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                February 17 2012
                February 17 2012
                : 335
                : 6070
                : 831-834
                Affiliations
                [1 ]Wyss Institute for Biologically Inspired Engineering and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
                Article
                10.1126/science.1214081
                22344439
                faa7f9ad-c13f-4b95-83cf-a4ec0d64cb35
                © 2012
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