Time To Put the Virus in Quarantine?

After 18 months spent confined to the interior of your home, the word "quarantine" may send shivers down your spine. Fear not – in new research from the Technical University of Munich (TUM), it is not we humans that look set to enter lockdown, it is the virus.

At TUM, the laboratory of Professor Hendrik Dietz in the Department of Physics explores the possibility of building molecular devices at the nanometer scale using different materials, including DNA. The group's latest research, published in Nature Materials, demonstrates their success in building icosahedral shells that can "trap" viral pathogens using DNA. "We propose a platform technology that considers trapping entire virus particles within de novo designed macromolecular shells to inhibit molecular interactions between viruses and host cells," the authors write.

Using DNA shells to fight viral pathogens may sound somewhat futuristic, but it addresses a very real and pertinent issue. One of the greatest challenges in the battle against SARS-CoV-2 has been identifying novel or repurposed drugs that can effectively treat COVID-19 symptoms. Unfortunately, these antiviral efforts have achieved minimal success, and this is not an issue unique to the coronavirus family. Seventy percent of all viruses listed by the World Health Organization do not have an effective treatment.

The new research by Dietz and colleagues contributes to the efforts of the VIROFIGHT consortium. VIROFIGHT is seeking new alternatives to fight against viruses, which include the nano-shells – or "virus traps" – made in the Dietz lab.

Technology Networks interviewed Christian Sigl, a member of the Dietz research team and first author of the new study. We wanted to know how virus traps are created, how they work as both a preventative and a treatment and why this approach could be the future approach to fighting infectious disease outbreaks.

Molly Campbell (MC): You propose a technology that considers trapping entire virus particles within de novo macromolecular shells. Can you describe where the idea came from?

Christian Sigl (CS): Initially, we studied the structure of viruses to guide the design and construction of our artificial nanoshells. During this research, we realized that some aspects of the adaptive immune system combat viruses by blocking the interaction between viruses and cells. Because our nanoshells feature cavities with similar sizes to viruses and form very thick shells, we suggested that the shells could have the capacity to neutralize viruses by blocking interactions with cells. We therefore designed shells with apertures that can trap entire virus particles. This resulted in the creation of a generic antiviral platform that could be applied to many different viruses.

MC: Can you explain how the concept of virus engulfing nanoshells would work? Would this be a preventive or a treatment for viral infection?

CS: An important step in the life cycle of a virus is the binding of the virus to cells. By trapping viruses inside our DNA nano-containers, they can no longer bind to cells, neutralizing the virus and inhibiting the viral infection.

We envision using the shells as both a preventive and treatment. In particular, the shells could be administered to people exposed to viral infections at high risk, like physicians, before they enter an endangered area. If they get exposed to viruses, the viruses are trapped inside the shells and can no longer infect the person. Simultaneously, nanoshells could be administered to already infected individuals to reduce the viral load and help mitigate the viral disease.

MC: In this study, you describe a programmable icosahedral canvas for the self-assembly of icosahedral shells. Can you describe how you designed the canvas and the shells in this study?

CS: Our design concept relies on the structure of viruses. We constructed triangles out of DNA with sizes that were a thousand times smaller than a human hair. These triangles are the building blocks of our artificial shells. The triangles feature a LEGO-like pattern on their edges, enabling multiple triangles to bind to each other and build the shells. By varying the shape of the triangles and the LEGO-like pattern, we could design shells with different sizes containing up to 180 triangles. Additionally, because of the rational design of the triangles, we fabricated shells with user-defined openings, which is needed for trapping viruses.

MC: How does the size of the shells that you created compare to the size of viruses generally?

CS: The size of the artificial DNA shells is comparable to the size of viruses. Many human viruses have sizes in the range of 20 nm to 200 nm. Our shells feature cavities ranging from 40 nm to 300 nm. Therefore, the majority of human viruses would fit inside the shell variants that we made.

MC: In the study, you were able to engulf the hepatitis B virus, inhibit its interactions and also neutralize infectious adeno-associated viruses exposed to human cells. Can you explain these results and what they mean in terms of demonstrating the robustness of the approach?

CS: Hepatitis B and adeno-associated viruses belong to different virus families. Both were successfully trapped and neutralized inside the shells. This demonstrates that the virus-trapping concept of our shells is not restricted to a specific type of virus but could be applied to various viral pathogens.

The shells feature cavities with sizes ranging from 40 nm to 300 nm. Moreover, we can easily swap the virus-binding molecules on the shells’ inside. As a result, the same shell platform can be used for many different viruses. To our knowledge, there is no antiviral drug that can target multiple different viruses.

MC: In theory, how would the viruses encapsulated then be disposed of or excreted, once encapsulated?

CS: Because we have not applied the shells to living organisms, my answer is mostly speculative. There are multiple approaches we consider. One is the activation of the immune system by the nanoshells. We can also mount different molecules on the inside and outside of the shells. For example, we could modify the shells with molecules that trigger the activation of immune cells that subsequently neutralize the shells together with the virus. It might also already be sufficient to trap viral particles inside the shells to reduce the viral load even if the virus particles eventually escape the shells. The trapping could delay proliferation of viruses and could give the immune system time to establish an immune response against the viral pathogen before a large quantity of new viruses is produced.

MC: Are there any other potential applications of the nanotraps, outside of encapsulating viruses?

CS: Besides trapping viruses, we are currently investigating a couple of other potential applications of the shells, including the use as antigen carriers for vaccination or drug delivery vehicles:

i) Our nanoshells have similar sizes and the same symmetry as many viruses. By mounting antigens on the outside of the shells, they could be applied as virus mimics for vaccination. 

ii) The shells feature large cavities and hence could serve as carriers for molecules of various sizes. They could, for example, be deployed for the delivery of genes for gene therapy or other large drug molecules.

MC: In your opinion, is this approach the future of dealing with infectious diseases?

CS: Our shell platform provides a novel generic antiviral platform. By small design changes, we can quickly adjust the shells to target different viruses, including new emerging viruses or virus strains. Consequently, the shells could provide a promising antiviral approach for existing viruses without an effective cure and future viral outbreaks.

MC: Are there any limitations to the work that you wish to highlight?

CS: We have not yet tested our nanoshells in living organisms. There might be adverse reactions. Testing the virus-neutralization of the nanoshells in mice is therefore the next crucial step.

MC: What are your next steps in this research space?

CS: In our work, we tested and proved the virus-neutralizing capacity of our shells in cell culture. In the next step, we will test our shells in living organisms, in particular mice. Additionally, we intend to test our shells for more different viruses, including viruses that cause severe illnesses in humans and lack an effective antiviral drug.

Christian Sigl was speaking to Molly Campbell, Science Writer for Technology Networks.