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Biomedicine

A Lockbox Built from DNA

Using DNA origami, researchers have assembled a nano-sized box with lock and key.

Using nothing but DNA, researchers in Denmark have constructed a tiny box with a lid that can either lock shut or–with the help of a set of DNA keys–hinge open. While other groups have experimented with using DNA origami to build three-dimensional objects, the new box, described in this week’s edition of Nature, is distinguished by its solid sides and moving parts.

Deoxyribose sugar cubes: Because complementary regions of DNA like to pair up, researchers were able to design a long strand of DNA that, combined with many tiny DNA staples, would automatically assemble itself into a nano-sized box. This technique is known as DNA origami. Here, the boxes were imaged using cryo-electron tomography to confirm their cubelike structures and hollow interior.

“It’s a rather beautiful molecular structure,” says John Reif, a distinguished professor of computer science at Duke University, who was not involved in the research. “It’s the first time that a nanostructure like that had a programmable and controllable lid.”

For now, the box serves as a proof of principle that DNA origami can be adapted to make elaborate three-dimensional structures, says Jørgen Kjems, a molecular biologist at the Aarhus University Center for DNA Nanotechnology, who led the research. But in the future, he believes that the nano-sized container could be adapted for a wide range of applications, from drug-delivery vehicle to logic gate.

DNA makes an ideal building material for nanostructures. It’s easy to churn out in bulk: Kjems and his team hijacked a virus to manufacture copies of the sequence that they designed. And it folds in straightforward, predictable ways according to its sequence. To design the box, the Aarhus team developed a computer program to generate a continuous single-stranded DNA sequence that, along with smaller DNA fragments that act as staples, would self-assemble into the desired shape.

The sequence was devised with many complementary regions so that it would automatically fold into six roughly square accordion-like sheets–the sides of the box–based on DNA’s natural tendency to pair into double strands. The DNA staples, also driven by the pairing of complementary sequences, stitched the sheets’ edges together to form a hollow cube with a hinged lid.

To make the lid lockable, Kjems and his colleagues fashioned two tiny DNA latches with sticky ends. Under normal circumstances, the latches adhere to the box, holding it shut. But when the two corresponding DNA keys are added, the latches bind to those instead, allowing the lid to swing open. A pair of dye molecules, one affixed to the box’s rim and another to its lid, glow red when close together and green when far apart, providing an easy way to detect whether a box is closed or open.

Think outside the box: The nano boxes, modeled here in gray, might one day ferry drugs to specific destinations in the body or serve as logic gates in a DNA-based computer. Each box’s lid is normally latched shut with two pairs of complementary DNA snippets (blue and orange). But when corresponding DNA keys (also blue and orange) are added to the mix, they interfere with the latches and allow the lids to swing open. Fluorescent dye markers glow red when a box is closed and green when it is open.

With three-dimensional structures such as this one, the real challenge isn’t designing the object but proving that it successfully formed, says Paul Rothemund, a computer scientist at the California Institute of Technology, who developed a simple technique for making DNA structures. The researchers used several different imaging methods to ensure that the boxes assembled themselves as planned. “They did a very convincing job of showing that they made what they thought they made, which is really important,” Rothemund says. “And now they’re free to try and elaborate on it and get it to actually do something.”

Kjems has several ideas for what the boxes might do. One possibility is to load them with drugs and program the lids to open in response to some biological cue inside the body–the presence of a virus or a cancer gene, for example–thereby releasing their therapeutic cargo.

“There’s a way in which they’re more interesting than almost any other nano-encapsulation scheme you can think of for that purpose, because they have these infinitely programmable lids,” says Rothemund. “That’s something that no other kind of nano-drug-delivery capsule can offer.”

Therapeutic uses are still a long way off, however. While the boxes are theoretically solid enough to prevent large molecules from leaking out and spacious enough to enclose a ribosome or a small virus, the researchers haven’t yet tried to put anything inside them. And so far, the boxes only function inside a test tube. Unlike some other nano-delivery vehicles, there’s no evidence yet of the safety or efficacy of DNA-based devices in living systems.

But the lockboxes needn’t carry a payload to prove useful. Kjems also envisions turning them into electronic components. Because they have two distinct keys, the boxes act as AND gates, opening (and glowing green) only when both keys are present. With a few straightforward tweaks, they could serve as NOT gates or OR gates as well. “In principle,” says Kjems, “you could build a DNA computer using these boxes.”

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