Wormed-shaped nanoparticles packed with DNA may be best at wiggling into sickened cells and delivering a genetic payload that combats disease, a new study shows.

“Worm-like nanoparticles offer higher stability in biological fluids as they can better avoid contact and clearance by macrophages. This will give these nanoparticles longer circulation time, and potentially improve their delivery efficiency to specific tissue targets,” said study author Hai-Quan Mao, a chemist and biomedical engineer at Johns Hopkins University in Baltimore, MD.

In a paper appearing online October 12 in Advanced Materials (1), Mao and his colleagues describe a method to make DNA nanoparticles shaped like worms, spheres, and rods. The shapes and sizes of the nanoparticles mimic the features of virus particles used for gene therapy, but they don’t carry any potential health risks.

To design the three different DNA nanoparticle shapes, Mao and his team made polymer structures with specific block lengths of positively charged molecules. These molecules interact with and condense DNA and polyethylene glycol, which serves as the protective coating for the genetic material. The team then exposed the polymer-packed DNA to the organic solvent dimethylformamide. The DNA recoils from this solvent, contracting into the specific shapes with the glycol armor around the genetic material to protect it from an immune-cell attack.

The shape the DNA nanoparticle takes depends on the ratio of organic solvent to water. More water meant more worm-shaped nanoparticles, while less water and more solvent created more spherical-shaped nanoparticles. To explain exactly how the different shapes developed, Mao teamed with Northwestern University physicist Erik Luijten, who developed molecular dynamics simulations of the biochemical reactions. The models suggest that the shape change is based upon a subtle competition between the DNA and the polyethylene glycol blocks. The polyethylene glycol blocks favor an expanded structure, while the DNA tends to favor a compact structure for the nanoparticle.

“At a sufficiently high concentration of the organic solvent, this tendency wins over the swollen structure favored by the polyethylene glycol, and compact, spherical particles result. In water, this tendency is not very strong and the nanoparticles take an expanded shape,” said Luijten.

The team tested the different-shaped DNA nanoparticles in rats and found 1600 times more gene expression in the animals’ livers with the worm-shaped particles compared to the rod- and sphere-shaped ones. The team is still not sure why, biochemically, the worm-shaped particles appear to be more effective. “We do not have all the answers to these questions yet, and are currently working on revealing the mechanism,” said Mao.

However, the researchers have now developed a more stable nanoparticle system and plan to link cell-recognizing molecules to the nanoparticle surfaces to enhance their cell-targeting ability. They also plan to apply the DNA nanoparticle system to a tumor model for cancer therapy.

Reference

1. Jiang, X. et al. 2012. Plasmid-Templated Shape Control of Condensed DNA–Block Copolymer Nanoparticles. Adv. Mater., Advanced Online: 1-6.