The process of fractal assembly. Animation: Grigory Tikhomirov, Philip Petersen, Lulu Qian; Narration: Lulu Qian; Music: Impromptu in Quarter by Kevin MacLeod CC BY 4.0

Images, even movies, created at the nano or atomic level are not new. Back in 2003, IBM introduced the smallest movie ever, “A Boy and His Atom,” made with carbon and oxygen atoms. Now, Caltech scientists have developed a method for creating comparatively large self-assembling DNA structures that can take on any desired custom pattern. To demonstrate their breakthrough, the team “painted” a replica of Leonardo da Vinci’s “Mona Lisa.”

This work builds on that of Paul Rothemund, a Caltech research professor, who developed the DNA origami technique in 2006. As the term “origami” indicates, DNA molecules fold themselves into prescribed shapes. This technique revolutionized nanotechnology, enabling construction of tiny devices, such as drug delivery systems, and programmable materials.

Until now, the size of these self-assembled images has been limited to about 0.05 square micrometers. The new research from the lab of Lulu Qian greatly expands the potential size and therefore the applications for origami-built images.

DNA makes a good substance for constructing nanometer-sized devices because the four nucleotides — cytosine (C), guanine (G), adenine (A) and thymine (T) — that constitute the nucleotide join together in strictly-prescribed sequences. For a given DNA strand, a second strand of smaller chunks of nucleotides can bond only at designated points, A with T or C with G. To fold a DNA strand, researchers combine a long single strand with shorter single strands called staples. The shorter strands bond to the longer one, causing it to bend.

To paint this large picture, Qian’s team divided the original Mona Lisa image into small square regions and built the corresponding image section into each square. Assembling these squares, or tiles, again relied on nucleotide bonding rules.

"We could make each tile with unique edge staples so that they could only bind to certain other tiles and self-assemble into a unique position in the superstructure," explains Grigory Tikhomirov, senior postdoctoral scholar and the paper's lead author, "but then we would have to have hundreds of unique edges, which would be not only very difficult to design but also extremely expensive to synthesize. We wanted to only use a small number of different edge staples but still get all the tiles in the right places."

The key turned out to be assembling the tiles in stages. Joining a few tiles into a regional group and then joining the groups simplified the process and ensured that joins are accurate. In the “Mona Lisa” project, researchers broke the image into 64 squares and put the folded DNA strands for each square into separate test tubes. Groups of four test tubes were mixed, then these four intermediate assemblies combined to form the final image. The researchers call the process “fractal assembly” since the same method is used at different scales.

"To make our technique readily accessible to other researchers who are interested in exploring applications using micrometer-scale flat DNA nanostructures, we developed an online software tool that converts the user's desired image to DNA strands and wet-lab protocols," says Qian. "The protocol can be directly read by a liquid-handling robot to automatically mix the DNA strands together. The DNA nanostructure can be assembled effortlessly."

The journal “Nature” published the research in its December 7, 2017, issue.