Scientists are reporting an advance in overcoming a major barrier to the use of the genetic material RNA in nanotechnology -- the field that involves building machines thousands of times smaller than the width of a human hair and now is dominated by its cousin, DNA. Their findings, which could speed the use of RNA nanotechnology for treating disease, appear in the journal ACS Nano.
Peixuan Guo and colleagues point out that DNA, the double-stranded genetic blueprint of life, and RNA, its single-stranded cousin, share common chemical features that can serve as building blocks for making nanostructures and nanodevices. In some ways, RNA even has advantages over DNA.
The scientists describe development of a highly stable RNA nanoparticle. They tested its ability to power the nano-sized biological motor of a certain bacteriophage -- a virus that infects bacteria -- that operates using molecules of RNA. The modified RNA showed excellent biological activity similar, even in the presence of high concentrations of enzymes that normally breakdown RNA.
For years, RNA has seemed an elusive tool in nanotechnology research -- easily manipulated into a variety of structures, yet susceptible to quick destruction when confronted with a commonly found enzyme.
"The enzyme RNase cuts RNA randomly into small pieces, very efficiently and within minutes," explains Peixuan Guo, PhD, Dane and Mary Louise Miller Endowed Chair and professor of biomedical engineering at the University of Cincinnati (UC). "Moreover, RNase is present everywhere, making the preparation of RNA in a lab extremely difficult."
But by replacing a chemical group in the macromolecule, Guo says he and fellow researchers have found a way to bypass RNase and create stable three-dimensional configurations of RNA, greatly expanding the possibilities for RNA in nanotechnology (the engineering of functional systems at the molecular scale).
In their work, Guo and his colleagues focused on the ribose rings that, together with alternating phosphate groups, form the backbone of RNA. By changing one section of the ribose ring, Guo and his team altered the structure of the molecule, making it unable to bind with RNase and able to resist degradation.
"RNase interaction with RNA requires a match of structural conformation," says Guo. "When RNA conformation has changed, the RNase cannot recognize RNA and the binding becomes an issue."
While he says previous researchers have shown this alteration makes RNA stable in a double helix, they did not study its potential to affect the folding of RNA into a three-dimensional structure necessary for nanotechnology.
After creating the RNA nanoparticle, Guo and his colleagues successfully used it to power the DNA packaging nanomotor of bacteriophage phi29, a virus that infects bacteria.
"We found that the modified RNA can fold into its 3-D structure appropriately, and can carry out its biological functions after modification," says Guo. "Our results demonstrate that it is practical to produce RNase-resistant, biologically active, and stable RNA for application in nanotechnology."
Because stable RNA molecules can be used to assemble a variety of nanostructures, Guo says they are an ideal tool to deliver targeted therapies to cancerous or viral-infected cells:
"RNA nanoparticles can be fabricated with a level of simplicity characteristic of DNA while possessing versatile structure and catalytic function similar to that of proteins. With this RNA modification, hopefully we can open new avenues of study in RNA nanotechnology."
The finding show that "it is practical to produce RNase (an enzyme that degrades RNA) resistant, biologically active, and stable RNA for application in nanotechnology," the article notes.
Guo serves as director of UC's National Institutes of Health (NIH) Nanomedicine Development Center and Nanobiomedical Center.
Co-authors include Jing Liu, Mathieu Cinier and Yi Shu from UC, Chaoping Chen from Colorado State University, Guanxin Shen from Huazhong University of Science and Technology in China, and Songchuan Guo from Kylin Therapeutics, Inc. This work was funded by grants from the NIH.
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