A team of chemists from McGill University has developed a new method for incorporating hydrophobic groups into nano-sized cubical cages made of DNA. The innovation allows these cages to encapsulate small molecules, opening the door for their potential use in drug delivery.

Hanadi Sleiman and her team specialize in creating short strands of custom-made DNA that self-assemble into unique macromolecular structures; a well-known accomplishment is the creation of cube-shaped cages. But the team is always looking to expand its creations. “Since we only have four bases to work with, it somewhat limits the types of structures we can make,” says Sleiman. The researchers were inspired by natural macromolecular structures like proteins.  Many proteins take advantage of the attraction between hydrophobic structures to join smaller modules into a larger, more complex whole. Sleiman and her team decided to try the same approach with their DNA nanostructures. 

In a paper recently published in Nature Chemistry, the team made molecules that consist of four hydrophobic alkyl chains connected by phosphate groups to a DNA strand. The strands hybridize into existing DNA cages, adding a hydrophobic ‘patch’ to one or more of the cube’s vertexes. If all the patches are on one face, two adjacent cubes can ‘shake hands’ to create a two-cube dimer.  

A team from McGill University has added hydrophobic patches (blue) to nanoscale cages made of DNA (grey/black). The original­ goal was to use hydrophobic attraction to join cages together, but in practice the groups aggregate­ inside the cage, creating­ a hydrophobic environment that can encapsulate drug molecules (purple). Addition of interfering DNA strands releases both the hydrophobic groups and the encapsulated molecules. Photo credit: Thomas Edwardson and Graham Hamblin 

However, when the team tried to make cubes with patches on both the top and the bottom, something unexpected happened. “Those eight hydrophobic patches met inside the cube,” says Sleiman. Although this prevented the addition of even more cubes to the structure, it also created a hydrophobic environment on the inside of the cube. This meant that the cages could now hold small molecules that would otherwise have slipped right through the holes. “We had no way to predict that,” says Sleiman. 

The team has proven the encapsulation behaviour with hydrophobic molecules like Nile Red and has even developed interfering strands that will release the cage’s contents on demand. Sleiman says they may have advantages over other drug delivery constructs. “They are biodegradable and, in many cases, DNA strands are not as immunogenic as other materials,” she says. “We can also control the size, shape and presentation of the ligands to a very high extent.” The team is already working with oncologists to test the cages on real cancer cells.