DNA folded into a nanocapsule for drug delivery

Researchers from Finland’s Aalto University and University of Jyväskylä have developed a customised DNA nanostructure that can perform a predefined task in human body-like conditions.

The team built a capsule-like carrier that opens and closes according to the pH level of the surrounding solution, and can be packed with a variety of cargo, closed for delivery and opened again through a subtle pH increase. Their work has been published in the journal ACS Nano.

“For quite some time I have wanted to build a dynamic DNA machine that would move with the help of an external stimulus, for example a biological cue,” said Veikko Linko, Adjunct Professor at Aalto University. “We picked up the concept of pH-responsive DNA strands from previous studies, developed the idea further, and demonstrated their applicability in a completely different setting.”

To make this happen, the team designed a capsule-like DNA origami structure functionalised with pH-responsive DNA strands. Such dynamic DNA nanodesigns are often controlled by the simple hydrogen bonding of two complementary DNA sequences. Here, one half of the capsule was equipped with specific double-stranded DNA domains that could further form a DNA triple helix — in other words a helical structure comprised of three, not just two DNA molecules — by attaching to a suitable single-stranded DNA in the other half.

“The triplex formation can happen only when the surrounding pH of the solution is right,” explained doctoral student Heini Ijäs, first author on the study. “We call these pH-responsive strands ‘pH latches’, because when the strands interact, they function similarly to their macroscopic counterparts and lock the capsule in a closed state. We included multiple motifs into our capsule design to facilitate the capsule opening/closing based on cooperative behaviour of the latches. The opening of the capsule is actually very rapid and requires only a slight pH increase in the solution.”

To harness the nanocapsules for transporting molecular payloads or therapeutic substances, the team designed the capsule with a cavity that could host different materials. They demonstrated that both gold nanoparticles and enzymes could be loaded (high pH) and encapsulated within the capsules (low pH) and again displayed (high pH). By monitoring the enzyme activity, the researchers found that the cargo remained fully functional over the course of the process.

“The most intriguing thing about the DNA origami capsules is that the threshold pH at which the opening and closing take place is fully adjustable by selecting the base sequences of the pH latches. We designed the threshold pH to be 7.2–7.3, close to the blood pH,” said Linko.

“In the future, this type of drug carrier could be optimised to selectively open inside specific cancer cells, which can maintain a higher pH than normal healthy ones.”

Further, the capsules remained functional at physiological magnesium and sodium concentrations, and in 10% blood plasma, and may continue to do so at even higher plasma concentrations. Together, these findings help pave the way for developing smart and fully programmable drug-delivery vehicles for nanomedicine.

Image left: The pH-responsive DNA origami nanocapsule (blue) loaded with an enzyme (yellow colour, high pH). The pH latches have two counterparts: a double-stranded domain (orange) and a single-stranded sequence (green). Image right: The DNA machine closes when pH is lowered, encapsulating the cargo with the help of triplex-forming latches. The capsule can be reopened and the cargo displayed with an increase in pH. Image credit: Veikko Linko, Boxuan Shen and Heini Ijäs/Aalto University.

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