DNA Nanorobot Targets Cells for Molecular Delivery

A paper just published in Science reports the successful design, construction, and testing of a nanorobot made of DNA¹. This achievement genuinely is food for the imagination, given the wide range of implications and the authors' interdisciplinary approach.

The nanorobot itself was constructed using a method called DNA origami. In short, the method uses a long piece of single-stranded DNA (ssDNA) called the "scaffold" and a collection of short ssDNA "staples." Large by nano standards, this nanorobot was built with a 7308-base scaffold and 196 staples. The staples base-pair with specific sites on the scaffold, contorting it into the desired shape.

The level of sophistication this paper shows can be achieved by DNA origami is remarkable. Guided by computer-aided design, the authors designed the staples required to build a hexagonal box with hinges, two locks, and docking sites on the inside for molecular payloads. Assembling the robot is as easy as mixing all the DNA together, heating it to 80°C, then cooling slowly to room temperature. The pieces of DNA moving randomly in the tube find their complementary sequence, latch on, and the robot folds into its most stable shape. Only in biology can you throw hundreds of parts together and expect an ordered, complicated product (imagine the computer you're using to read this self-assembling from its parts!).

So far, our nanorobot sounds more like a miniature sculpture than a robot, so let's add the payload. The team tested two kinds: gold nanoparticles and antibody fragments. In either case, the cargo had to be bound to a short DNA molecule with a sequence complementary to that of the docking sites within the nanorobot. Using this method, they found that on average, nanorobots were loaded with 4 gold nanoparticles, out of a possible 12. The corresponding figure for the antibody experiment was 3 of 12. That's pretty impressive, given that this is a brand new technology.

The real appeal of the nanorobot, though, is its two locks made of aptamers. Aptamers are DNA (or RNA) molecules that change shape when they encounter a non-nucleic acid molecule, a surprising feat. The aptamers used in the nanorobot unlatch the door, so that the two halves can (moving randomly) pivot on the intact hinges on the other side like a clamshell. By using two different kinds of aptamers for the two locks, one can build a logical AND gate. AND gates, like all logic gates, take two inputs, each being either 1 or 0. AND gates produce an output of 1 only if both inputs are also 1. Here, input means small molecule changing aptamer shape, and output means unhinging of the robot. Only if both locks are undone will the nanorobot open to reveal its payload.

The applications of this piece of molecular engineering are potentially quite extensive. The largest and most obvious example is drug delivery. When taking medication, we are exposing our entire bodies—not just the ailed portions—to the drug. In some cases this isn't problematic, or is perhaps even desirable, but it makes side effects an unavoidable reality. The clearest example is probably chemotherapy, which has severe and body-wide side effects. It would be revolutionary if the drug only found its way into tumor cells, leaving the rest of the body alone and healthy. In their paper, the team demonstrated that their nanorobots could distinguish between different kinds of cancer cells, so the first step is already within reach. My knowledge of chemistry isn't great, but I can't think of why any drug couldn't be carried as nanorobot payload, perhaps with some tweaks. Ideas like these are paving the way to an exciting future of medicine driven by synthetic biology and rational design.

For a video summarizing this finding with author commentary, click here.

Image Credit: Campbell Strong, Shawn Douglas, & Gaël McGill (via Wyss Institute)

Reference:

1. Douglas, S. M., Bachelet, I., & Church, G. M. A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads. Science 335, 831–834 (2012).