Team finds stable RNA nano-scaffold within virus core
With the discovery of a RNA nano-scaffold that remains unusually stable in the body, researchers at the University of Cincinnati (UC) have overcome another barrier to the development of therapeutic RNA nanotechnology.
Peixuan Guo, PhD, Dane and Mary Louise Miller Endowed Chair and professor of biomedical engineering, and his colleagues in UC's College of Engineering and Applied Sciences report the construction of a thermodynamically stable RNA nanoparticle online in the journal Nature Nanotechnology.
The nanoparticle, constructed from a three-way junction (3WJ) motif of packaging RNA (pRNA) molecules, can serve as a platform for building larger, multifunctional nanoparticles, says Guo, which can then be injected into the body to deliver therapeutics to targeted cells.
"RNA nanoparticles have applications in treating cancers and viral infections," he says, "but one of the problems in the field is that RNA nanoparticles are relatively unstable. Without covalent bonds or cross-linking to keep them together, the nanoparticles produced via self assembly can dissociate when injected into animal and human circulation systems, where they exist at very low concentrations."
In the work, Guo and researchers explored the unique structure of the DNA packaging motor of bacteriophage phi29, a virus that infects bacteria. The motor is geared by a ring of pRNA molecules containing interlocking loops and helical domains, which are joined together by a strong 3WJ motif.
"The pRNA is extraordinary strong," says Guo, "since it is a mechanical part that nature uses to gear a powerful motor. This strength makes it an ideal platform for constructing RNA nanoparticles. Furthermore, the core has unique and unusually stable features, such as resistance to strong denaturants like urea and the ability remains intact at ultra-low concentrations in the absence of magnesium."
Using three small fragments of RNA with high affinity for assembling into larger structures, researchers were able to recreate the 3WJ core outside the pRNA structure. In addition, each arm of the 3WJ core can be fused to siRNA molecules, receptor-binding ligands and RNA aptamers, molecular tools necessary for the nanoparticle to find a targeted cell inside the body and silence genes within it.
The resulting nanoparticle remained stable and functional in vitro and, when introduced in vivo, targeted tumors specifically without diffusing to other critical organs or normal tissues.
"Making fusion complexes of DNA or RNA is not hard," says Guo, "but ensuring the appropriate folding of individual modules within the complex to retain their function after fusion is a difficult task. The pRNA 3WJ core directs the folding of individual functional modules, and the stability of the 3WJ core ensures that each fusion module remain folded for proper function."
Earlier this year, Guo and his team overcame another obstacle to RNA nanotechnology, the risk posed by RNase, a common enzyme that quickly degrades RNA upon contact. By replacing a chemical group in RNA's ribose ring, Guo's team was able to make the RNA resistant to degradation, while retaining its ability to assemble into nanoparticles and form appropriate 3D structure and function.
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University of Cincinnati Academic Health Center: http://www.healthnews.uc.edu
Thanks to University of Cincinnati Academic Health Center for this article.
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Source: http://www.labspaces.net/113285/Team_finds_stable_RNA_nano_scaffold_within_virus_core
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On Sunday September 11, 2011, on the ten year anniversary of the terrorist attacks on 9-11, Americans watched as survivors, politicians, and family members mourned/remembered the victims of that attack. On the other side of the world a large truck full of firewood pulled in front of Combat Outpost Sayed Abad in eastern Wardak province in central Afghanistan. While the protective barrier absorbed the blast, guarding against U.S. deaths, the bomb still wounded 77 American troops. Watching the remembrances in New York, Pennsylvania, and Washington D.C., feelings of remorse, pity, sympathy, sadness, and more entered the collective minds of the nation, but did a strange feeling of ?that?s all they could do,? quietly creep in as well? With a can-do grandiose attitude typical of Americans, construction of the World Trade Centers, the soon-to-be largest buildings in the world began on August 5, 1966. Using 1960?/70?s technology and equipment, the builders finished both towers by July 1973. It took people forty years ago, just seven years to complete this massive building project! Each time they appeared on television or someone stood at their base and felt vertigo just looking as the sun-kissed towers seemingly touched the clouds, he/she had to feel an overwhelming sense of pride in a nation capable of such beauty and inclusion into the skyline. Which is just one of the reasons the nation collectively wept at more than just the loss of life, it was an attack on the very foundational pride of our nation, a seeming metaphor for the crumbling of our society. Americans rightfully weep at the injury of even one soldier. Seventy-seven sons, daughters, fathers, mothers, brothers, and sisters, wounded makes even the most hardened of people distressed. 


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