Nanotechnology help New Ways to Fight an Endless Pandemic
The Executive Headlines
A flurry of recent papers highlights growing interest in approaches that employ nanomaterials as antiviral countermeasures. Compared with traditional small molecules or antibodies that inhibit viral replication or cellular entry, nanotechnology offers drug developers a suite of measures that may complement antiviral measures. They include virus binders, cell-membrane decoys or viral-envelope inhibitors. With the help of an influx of funding spurred by the COVID-19 pandemic, some researchers hope that these materials could soon move towards clinical translation.
Nanostructure-based COVID-19 Management
Nanostructured material is a type of material with at least one nanometric dimension (usually less than 100 nm). They can be organic, inorganic, biomaterial-based, and carbon-based Their physicochemical properties such as, chemical reactivity, size-dependent transport, biocompatibility, and reduced toxicity attracted scientists in many fields. Medicine is one such fields with rising attention in applying nanotechnology. Nanostructure-based delivery systems demonstrated improved specificity and bioavailability over the traditional system. Much of the added value is related to NP physicochemical properties which include controllable size, great surface area to mass ratio, and easily functionalizable structure. They can stabilize the drug in the systemic circulation for targeted, controlled, and sustained delivery, which, as a result, can increase the therapeutic advantage. Multiple targeting, in vivo imaging, and combined drug delivery are also their potential advantages. All these principles can be applied to fighting the COVID-19 pandemic.
Why Nanostructure-based COVID-19 Management?
As the pandemic continues to cause an enormous global crisis, there is still an unmet need to discern a favorable, safe, and typically effective approach for diagnosis, treatment, vaccination, and prevention to prohibit super-spreading of the virus and a mortality crisis. Diverse nanotechnological strategies have shown a promising capacity to address many of those unmet needs in the fight against the pandemic as stated in the next sections.
Challenges in Biosafety
COVID-19 exposed the world for too many discrepancies including an absence of effective vaccines and therapeutics, lack of rapid or real-time detection methods, shortage of protective equipment, and limitation in accessibility of support for infected patients. These biosafety problems arise mainly from limited research and considerations in materials science. A variety of nanostructured materials, such as polymers, inorganic-organic frameworks, biomaterials, graphene derivatives, and carbon nanotubes are radically transforming the way of countering biosafety challenges.
Nanomaterials have already played a key role in the fight against SARS-CoV-2. The Pfizer–BioNtech and Moderna vaccines both rely on lipid nanoparticles to carry mRNA into cells. Nanoparticles are also showing promise as vehicles for small-molecule antiviral drugs, building on decades of progress with nanoscale drug-delivery systems.
Now the urgency of the COVID-19 pandemic is generating interest in therapeutic nanomaterials that can themselves halt viruses in their tracks, rather than just acting as delivery vehicles for drugs or vaccines. “A lot of these nanomaterials are being developed to engage with the virus particles directly, either disrupting them or binding to them,” says Joshua A. Jackman of Sungkyunkwan University in South Korea.
Unlike traditional therapeutics, which tend to target a specific viral species and may lose their efficacy as the virus accumulates mutations, antiviral nanomaterials target chemical and physical properties common to many types of virus. Some of these nanomaterials may offer advantages in the context of pandemic countermeasures, as they can potentially be formulated quickly and have activity across a broad range of virus families.
Much of this work is still confined to academic labs, although a handful of companies are developing antiviral nanomaterials. But the ravages of COVID-19—and the clear need to prepare for future viral pandemics—are opening up fresh opportunities.
In June, for example, the Biden administration launched the Antiviral Program for Pandemics, with $3 billion for research into new antivirals that can tackle SARS-CoV-2 and other viruses with pandemic potential. “This new funding stream will definitely stimulate and support more research and development in the area of antiviral nanomaterials,” says Liangfang Zhang at the University of California, San Diego. “COVID has really changed the landscape, we see that we really need more ready-made solutions for emerging viruses.”
Because many viruses rely on proteins linked to sugars (glycoproteins) on their surface to bind to molecules on host cells, nanomaterials that mimic these cellular attachment points can potentially act as antivirals. Zhang is making ‘nanosponges’ that use this approach to intercept viruses. To make the nanosponges, Zhang’s team starts with human cells such as red blood cells or immune cells known as macrophages. After removing the contents of the cell to leave only the membrane, they break the membrane into thousands of tiny sacs, or vesicles, roughly 100 nanometers wide. Then they add nanoparticles made from a biocompatible and biodegradable polymer, such as poly(lactic-co-glycolic acid). Each nanoparticle becomes coated with a cell membrane, forming a stable core-shell structure that acts as a decoy of a human cell. The nanosponges then use binding points on their membranes to surround a virus and prevent it from entering host cells.
These nanosponges are effective against a range of viruses and bacteria in vivo, and Zhang’s San Diego-based spin-out company Cellics Therapeutics plans to begin a clinical trial next year of its lead candidate, a nanosponge carrying a red blood cell membrane that is effective against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Cellics is also using macrophage membranes to develop similar nanosponges with antiviral activity. “There are many different types of virus, and each virus may have different variants,” Zhang says, “but regardless of that, in order to infect humans they need to interact with the host’s cells through receptors.”
Last year, Zhang found that a cellular nanosponge coated in membranes derived from human lung epithelial type II cells or human macrophages were both able to trap SARS-CoV-2 and prevent infection in vitro. The membranes on these nanosponges sport the receptors angiotensin-converting enzyme 2 (ACE2) and CD147, to which SARS-CoV-2 binds during infection. Zhang’s team also has unpublished results from an in vivo study with mice, showing efficacy against the coronavirus and no evidence of toxicity.
Starpharma, headquartered in Abbotsford, Melbourne, Australia, is also mimicking host cells to combat viruses. It makes synthetic polymers with a branched structure, known as dendrimers, that are roughly 3 to 4 nanometers wide. The outer surface of each dendrimer is covered in naphthalene disulfonate groups, similar to the heparan sulfate proteoglycans found on host cell membranes, molecules to which many viruses stick to.
Starpharma already has products on the market that employ a dendrimer called SPL7013 as an external barrier against viruses and bacteria. SPL7013 is used in VivaGel, a lubricant in condoms, for example. Earlier this year, Starpharma launched Viraleze, a broad-spectrum antiviral nasal spray containing SPL7013, which is registered for sale as a medical device in Europe and India. However, sales of Viraleze in the U.K. were halted in June after the U.K. Medicines and Healthcare products Regulatory Agency raised concerns about the product’s marketing claims.
In August, the company unveiled research showing that Viraleze prevented SARS-CoV-2 infection in a mouse model. Administering the nasal spray before and after exposure to SARS-CoV-2 reduced viral loads in the animals’ blood, lungs and trachea by more than 99 percent. The company says that a clinical safety study, which has not yet been peer reviewed, showed that the dendrimer in Viraleze was not absorbed in the body and caused no significant side effects.
Star-shaped DNA scaffolds offer another potential approach. Xing Wang at the University of Illinois at Urbana-Champaign has built such structures carrying DNA aptamers—single stranded DNA molecules—capable of binding to antigens at multiple points on the surface of dengue fever virus. The physical bulk of the DNA star, and its negative charge, prevent the virus from latching on to host cells, shutting down infection. The team also has in vitro data, currently being peer reviewed, showing that certain DNA stars can inhibit SARS-CoV-2 infection.
The researchers designed triangular DNA structures that assemble into shells of various shapes and sizes, from 90 to 300 nanometers wide. By tweaking the DNA sequences in the triangular building blocks, they created virus-sized openings in the side of a shell. In vitro experiments showed that these shells could bind viruses such as adeno-associated virus serotype 2 and prevent them from infecting human cells. “The advantage of our shells is the number of virus binders we can attach, and also that we can switch the virus binders very easily,” says Christian Sigl, a PhD student in Dietz’s lab who carried out the experimental work. This means the shells could in principle be tailored to bind any virus, he says. Dietz is the coordinator of a €3.9-million project called Virofight, which launched in June 2020 with funding from the European Commission, to build a shell to trap SARS-CoV-2 and test the strategy in mice.