Breaking Down Virus Shells to Improve Therapy Deliveries

Rice University researchers have found that breaking down a virus’s tough outer shell creates nanoparticles that could improve the delivery of chemotherapies and other medicines to diseased cells.

by John Tibbetts
March 26, 2018

Researchers have found that breaking down a virus’s tough outer shell creates nanoparticles that could improve the delivery of chemotherapies and other medicines to diseased cells.

Viruses have evolved over millions of years to invade cells efficiently. Scientists have taken advantage of that ability by using benign adeno-associated viruses (AAVs) as carriers to insert gene therapy payloads into diseased cells. Biotech companies, in turn, are now investigating a number of natural AAV variants for use in gene and cell therapies. 

Each AAV variant has a different structure that provides a signal that allows it to enter specific targeted tissues or organs. Scientists direct the variants to find their way into cell nuclei and deliver DNA and other nucleic acids to treat disease. What’s needed are more efficient ways to deliver the nucleic acids into the host cells.

Junghae Suh, an associate professor of bioengineering at Rice University, and her team of researchers attempted that by conducting research to find out how the capsids reconfigure themselves when manipulated or triggered by external stimuli. That’s something, she says, that others before her had not been able to figure out.

As a result of the research, Suh’s team has developed viruses that can be triggered by light or by extracellular proteases associated with certain diseases to improve the efficiency and accuracy of payload deliveries. The team is also learning how to use AAVs to carry therapeutic payloads in applications that extend beyond gene therapy.

“Scientists have developed many drugs based on peptides [small proteins], but there aren’t great delivery mechanisms for this purpose,” Suh says. “If you sprinkle peptides onto cells, most just hang around. They don’t enter cells very efficiently."

“We’re saying that we could reprogram AAVs to deliver peptide-based drugs to control cell behavior,” Suh adds. “We’re taking the virus’s inherent ability to get inside cells by tweaking and improving it. The idea is to deliver peptide therapeutics more precisely and efficiently.”

Suh, along with Nicole Thadani, a Rice graduate student and lead author of the paper, and the rest of the team are taking advantage of AAVs’ natural ability to reshape themselves after they enter a cell. Their research was published in the American Chemical Society journal ACS Nano.

In its natural state outside of a cell, an AAV holds its peptides locked tightly inside the capsid. But once the virus has invaded a cell, this shell can change its structure. “Viruses are primitive shape shifters,” Suh says. “Some viruses have very dramatic shape-shifting and others have more subtle changes in their overall structure.”

When an AAV enters a cell, it finds itself in the endosome, a sorting compartment for various cargo. “The virus senses the endosome’s environmental conditions, including low pH and other factors that we have yet to identify.”

The new environment triggers a physical change in the AAV capsid, which breaks down and transitions from a ball-like state to a “brushy” one. From its shell, out pops tiny hair-like strands containing functional peptides. Those peptides create membrane pores that allow the virus to escape the compartment and eventually make its way to the cell’s nucleus.    

The researchers are repurposing AAV’s shape-shifting process, allowing the release of additional peptides from the capsid surface. The team created altered versions of the proteins that self-assemble to form the virus capsid.

Their novel process increased the number of peptides displayed on the capsid surface, resulting in the generation of nanodevices that have never been seen before in nature. Based on previous research, the researchers inserted a common tag that made it easy to monitor the peptides. The tags are hidden during the virus’s pre-stimulated form, in their “off” state, before the virus has entered a cell. When the peptides are activated in an endosome, these tagged peptides are displayed on the surface of the virus, so the researchers could track them.

The researchers are now studying how to bind therapeutic peptides and other medicines to the exposed hairy loose ends at the capsid surface. The next phase of the project is to insert known peptide drugs into cells. The goal is to test whether this platform can be effective in delivering more therapeutically relevant peptides into cells for the purpose of drug discovery. 

 “We are leveraging the virus’s ability to do this conformational change from the ball state to the hairy state. The next phase is to test inserting therapeutic peptide drugs into the virus by attaching them to the loose ends,” Suh says. “You could also mix peptides and nucleic acid delivery, mixing chemotherapies with gene therapies with the same delivery platform.”

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