Biomedical engineers experiment with nano DNA origami on mice to eventually prevent acute kidney failure in humans.
A long strand of DNA folded into a nano-sized rectangle has been found to protect mice from acute kidney failure and could eventually do the same for humans.
Researchers have been folding DNA into nano-sized shapes, a technique called DNA origami, since the 1980s. They typically start with a long single strand of DNA and then use dozens of short single strands of DNA, called staples, to bind certain regions of the long strand together. This binding bends the DNA into a desired shape. Researchers control that shape by tailoring the sequences of the short staple strands to bind only to specific sites using computer programs. To show the versatility of DNA origami, researchers have folded DNA into a 2D smiley face, a hollow cube, and a 3D teddy bear.
“We have so many structures in hand, but what can we do with it for biomedical applications?” asked Dawei Jiang, a postdoctoral fellow at the University of Wisconsin-Madison, and one of the authors of a recent paper that details the new research.
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Quite a lot, it seems. Several features inherent to DNA origami make it an intriguing nanomaterial for drug delivery or medical imaging, yet few studies have examined how it behaves in the body. By its very nature, DNA origami is biocompatible and biodegradable. The high degree of control over the shape of DNA origami offers researchers a unique ability to influence where the nanomaterial travels in the body.
The researchers specifically studied whether DNA origami could reduce the rapid buildup of reactive oxidative species, nitrogenous chemicals that damage kidney cells when they accumulate in urine.
The team, which included Jiang, Peng Huang of Shenzhen University, Chunhai Fan of Shanghai Jiao Tong University, Hao Yan of Arizona State University, and Weibo Cai of University of Wisconsin–Madison, recently published their findings in Nature Biomedical Engineering.
In this proof-of-concept study, they demonstrated several aspects of a successful therapeutic delivery system: The DNA origami is stable enough to reach its target organ, is as effective as a commonly used drug, and does not generate an immune response.
They started with an M13 virus, which has only a single strand of DNA (as opposed to the more usual double stranded helix). They then stapled a variety of DNA strands into 2D rectangles, 2D triangles, and tubes. Finally, the researchers attached radioactive copper-64 to the nanostructures so they could use medical imaging to see where the structures were inside a mouse.
Three hours after injection, the researchers imaged the mice using positron emission tomography (PET). Each DNA origami shape localized in the kidneys, while partially folded or unfolded M13 DNA stayed mainly in the liver.
“This was really interesting,” Jiang said. “I looked in the literature and I did not find any nanostructure that went to the kidneys so specifically.”
Still, he wondered how this specific localization could be useful. Jiang shared his result with a doctor working in a neighboring lab, and the doctor mentioned that acute kidney failure could be recreated in mice. He theorized that the DNA could neutralize the reactive oxidative species building up in the urine.
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In humans, acute kidney failure happens suddenly, and waste products that accumulate within hours can be fatal. Jiang and his colleagues recreated acute kidney injury in mice caused by damaged muscle. They then injected radiolabeled rectangular DNA origami into these mice and again they saw the DNA origami localize in the kidneys.
Next, the researchers used a form of PET imaging commonly used to assess kidney function in real time. They found that mice injected with DNA origami had better kidney function than those injected with unfolded DNA. Surprisingly, kidney function in DNA-origami-treated mice was actually comparable to that of mice given high doses of N-acetylcysteine, a common drug for acute kidney failure.
Jiang and colleagues also ran a test on cultured human kidney cells to which they added hydrogen peroxide to reproduce the toxic combination of hydrogen peroxide, hydroxyl radicals, and oxygen radicals found during renal failure. They found that 80 percent of cells survived after 24 hours. Without the DNA origami, only 50 percent survived. Instead of the reactive hydrogen peroxide attacking DNA in kidney cells, it attacked the DNA origami, Jiang says.
In the future, he wants to learn more about why DNA origami travels preferentially to the kidneys. Jiang is also interested in testing it as a treatment for other causes of acute kidney injury. He’ll also explore if this method could also be used as a general treatment for other diseases that generate reactive oxidizing molecules.
Veikko Linko, who develops DNA origami drug delivery systems at Aalto University in Finland, thinks this work “is an important step towards DNA origami-based real-life applications that may open up new avenues in bionanomedicine.”
Melissae Fellet is an independent writer.
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