Learning when to fold

Researchers utilize nucleic acid origami to achieve better RNA interference

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CAMBRIDGE, Mass.—RNA interference has long since been anattractive method for potential therapeutics, offering the chance to use cells'natural method to control gene expression. Previous methods have consisted ofattempts to deliver RNA via particles made of polymers or lipids, but a team ofresearchers at the Massachusetts Institute of Technology (MIT), AlnylamPharmaceuticals and Harvard Medical School has crafted new particles withbetter results, based on a technique known as "nucleic acid origami."
These new particles seem to overcome the safety risks andtargeting difficulties associated with existing particles, according to DanielAnderson, associate professor of health sciences and technology and chemicalengineering and a member of the David H. Koch Institute for Integrative CancerResearch at MIT.
The nanoparticles are constructed from DNA and RNA and allowresearchers to turn off genes expressed in cancer cells. They are biodegradableand have no potential to harm the body, unlike currently used particles, andcan be tagged with folate (vitamin B9) molecules in order to target thenumerous folate receptors found on some tumors.
"Control of nanoparticle shape and size has been shown to beimportant for function. Origami methodshave been developed to make all kinds of interesting shapes," says Anderson, asenior author of a recent paper on the team's work. "We reasoned that usingorigami we could make a siRNA delivery particles that were all the same,biocompatible and biodegradable (because they are made of nucleic acid), smallbut large enough to avoid renal filtration (so they could circulate longer butstill penetrate tissues) and labeled with ligands, to facilitate their specificdelivery. We were surprised in the case of folate that no obvious endosomalescape methods needed to be included."
RNA interference is the method by which short interferingRNA (siRNA) interrupts the transference of genetic information from DNA toribosomes by binding to the messenger RNA molecules carrying DNA instructionsand destroying them before they reach the ribosome.
Anderson and his colleagues built their nanoparticles byusing nucleic acid origami, which enables the construction of 3D shapes usingshort segments of DNA. The team fused six strands of DNA to create atetrahedron, with three folate molecules on each particle and a single strandof RNA attached to each edge of the shape.
"What's particularly exciting about nucleic acid origami isthe fact that you can make molecularly identical particles and define thelocation of every single atom," said Anderson in a press release.
The lipid, lipid-like or polymeric materials that are currentlyused are effective, but tend to result in larger particles, Anderson notes, andmight be associated with toxicity. In addition, such particles areheterogeneous, he adds, "a collection of particles within a certain size rangeand composition." The origami particles the team has constructed, however, aremonodisperse and molecularly identical, which Anderson says allows them to"control the shape and ligand presentation within the particle in a way wecan't do with self-assembling particles."
In mouse studies, the nucleic acid nanoparticles were shownto circulate in the bloodstream with a half-life of 24 minutes, which gave themenough time to reach their targets. According to Anderson, the DNA tetrahedronappeared to protect the RNA from being rapidly absorbed and excreted by thekidneys. The nanoparticles also effectively accumulated at the tumor sites. TheRNA attached to the tetrahedrons was designed to target a gene for luciferase,which had been added to the tumors to make them glow, and in treated mice,luciferase activity was more than cut in half.
The next step for the research is to spread out intotargeting other genes and other genetic diseases.
"We are looking at the utility of these particles in othertumors, in particular ovarian, and with other ligands, and also optimizingtheir size and shape," says Anderson.
Theresearch was funded by the National Institutes of Health, the Center for CancerNanotechnology Excellence, Alnylam Pharmaceuticals and the National ResearchFoundation of Korea, and appeared in the June 3 issue of Nature Nanotechnology. The paper's lead author is Hyukjin Lee, aformer MIT postdoctoral and current assistant professor at Ewha WomansUniversity in Seoul, South Korea.

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