A new computer model that allows biological engineers to design the most complex 3D DNA structures ever made takes 3D DNA origami to a new level. The advance could help scientists probe some of the tiniest processes of biology – such as photosynthesis. It could also help create new types of drugs or RNA therapies – an emerging frontier of personalized treatment for diseases like cancer.

complex 3D DNA shapesShare on Pinterest
The computer model allows biological engineers to exercise nanometer-scale control to build complex 3D DNA shapes.
Image credits: Top row – Stavros Gaitanaros (MIT) & Fei Zhang (Arizona State University); Bottom row – Keyao Pan (MIT) & Nature Communications

In the journal Nature Communications, a team of researchers, including members from the Massachusetts Institute of Technology (MIT), describe how they designed the computer model and used it create elaborate 3D DNA shapes, including rings, bowls and icosahedrons that have structures similar to viruses.

As scientists get better and better at probing and manipulating matter at the scale of individual atoms and within molecules – the realm of nanotechnology – so grow the opportunities for biological engineers to use DNA as a nanoscale building material.

DNA is stable, and scientists can easily program it by changing the sequence of its building blocks. But the function of DNA relies not only on the sequences of its chemical subunits, but also on its shape. So, about 10 years ago, scientists started manipulating DNA in two dimensions – and gave rise to the term “DNA origami.”

The 2D DNA shapes were made by binding “staple strands” to “DNA scaffolds.” Later, scientists combined this method with nanotechnology and began to work with 3D DNA origami. This led to suggestions that 3D DNA nanostructures could one day be used to deliver drugs, act as biosensors, perform artificial photosynthesis and more.

The more complex the structure that can be designed, the more promising the range of applications that the technology offers. With this latest model, for example, the MIT-led team believes researchers will be able to build DNA scaffolds that anchor arrays of proteins to build new vehicles for RNA therapies and chromophores or light-sensitive molecules to mimic plant photosynthesis.

Senior author Mark Bathe, an associate professor of biological engineering at MIT, explains the step forward that their study represents in the field of 3D DNA origami:

The general idea is to spatially organize proteins, chromophores, RNAs and nanoparticles with nanometer-scale precision using DNA. The precise nanometer-scale control that we have over 3D architecture is what is centrally unique in this approach.”

The progress toward the new model has been slow and painstaking. In 2011, the team developed a model called CanDo to create 3D DNA shapes – but it could only make a limited range based on rectangular or hexagonal close-packed lattices of DNA bundles.

This latest version uses a new algorithm that helps the team create much more complex structures than were previously possible. It can take sequences of DNA scaffold and staple strands and predict the 3D structure of virtually any programmed DNA sequences.

Prof. Bathe says predicting the 3D structure in the model “is central to diverse functional applications we’re pursuing, since ultimately it is 3D structure that gives rise to function, not DNA sequence alone.”

The new model works by cutting DNA sequences into subunits called “multiway junctions” – essential building blocks of programmed DNA nanostructures, similar to those that form naturally during DNA replication. Multiway junctions are what allow DNA strands to cross over and bind to the strand of an adjacent DNA helix when they unwind and form new pairs during replication.

The computer model then re-assembles the cut-up DNA into larger programmed, nanoscale shapes such as rings, discs and spherical containers. Re-programming the sequences of these components allows DNA origami designers to easily create complex architectures, including symmetrical cages shaped like tetrahedrons, octahedrons and dodecahedrons.

Prof. Bathe explains that the 3D DNA shapes are just “passive scaffolds.” Their function comes from the other molecules that can be attached to them and provide a range of applications.

One example the team is working on is trying to mimic the protein scaffold structure that allows living plant cells to carry out photosynthesis. Protein scaffolds are harder to engineer into nanoscale assemblies – so the 3D DNA origami method provides a useful alternative. The scientists can attach chromophores to the DNA scaffold instead, in order to create the key structures for photosynthesis.

The video from MIT below further explains how the new model works:

Other applications are also possible – such as scaffolds that allow scientists to mimic bacterial toxins so they can create versions that are non-toxic that they can use to deliver RNA therapies directly into cells.

Using DNA scaffolds to carry therapeutics like microRNAs, mRNAs and cancer drugs, it is possible to get into cells without setting off a lot of alarms or degrading the cell machinery, Prof. Bathe explains.

The team plans to make their algorithm publicly available so other DNA designers can use it. They first want to improve the model so designers can simply give it a specific shape and obtain the sequence that will produce that shape.

Such an enhancement would enable true nanometer-scale 3D printing, where the “ink” is synthetic DNA, says the team.

Funds for the study came from the Office of Naval Research and the National Science Foundation.