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If bacteria had a literary hero, Neil Gaiman would be it. The mantra of the evil little creature in his children's novel Coraline exactly captures what microbes in a biofilm would sing: “We are small, but we are many.”

The main challenge that biofilms—defined as a microbial community that colonizes a surface—pose for researchers is that they are difficult to target because the bacteria surround themselves with a polymeric substance that prevents access to their surface proteins by anything larger than a few nanometers. This difficulty translates to a clinical problem, in that biofilms are difficult to diagnose at an early stage, and often the only treatment option is surgery.

Mark Young and Trevor Douglas from Montana State University have experience in aiming for other clinically challenging targets—tumors—using viral platforms. Together with Peter Suci, a research fellow in their laboratories, they saw parallels in the structure of a tumor and a biofilm, and decided to also try a viral targeting strategy for biofilms. Young describes the basic strategy: “You take a nanoplatform, a virus, put a targeting moiety on the outside and deliver it to a cell.”

They used a plant virus that produces a noninfectious symmetrical protein cage assembled from 180 identical subunits. This gives them exact spatial control over any agent that is linked to these subunits. To target a biofilm made up of Staphylococcus aureus, they first bound the protein A on the bacterial cell surface with a biotinylated antibody and then linked a biotinylated viral cage, bearing a magnetic resonance imaging (MRI) contrast agent, to it via a streptavidin molecule.

They could tightly pack the surface of bacteria with viral cages (Fig. 1) and also achieved deep penetration of the biofilm, demonstrated by MRI. Young says that the plant virus balances the requirements for high cargo capacity to achieve good payload and small size; the viral cage allows multivalent presentation of a binding ligand on a single platform resulting in high affinity and with its 28-nm diameter it is not too large to penetrate the biofilm.

Figure 1: Virus targets bacteria.
figure 1

S. aureus bacteria are covered by a viral cage that specifically targets the surface of the bacteria. Scale bars, 200 nm (left), 100 nm (right). Reprinted with permission from Elsevier.

So far Douglas, Young and their teams performed all experiments on a biofilm grown in a test tube, not in vivo, but this is clearly the end goal of their research. As Douglas says, “the goal is a multifunctional material, combining both imaging and therapeutic capacity.”

To achieve the latter they are working on delivering an activatable compound that diffuses out of the protein cage and destroys the biofilm. Douglas has no illusions as to the challenges ahead. Since they are working with biomaterials, interactions with the immune system are to be expected, and he cautions: “It is not a 'plug-and-play' system at this point; you need to tailor the immune response to the particular pharmacokinetic response that you want.” Young puts their goal in more generic terms: “Our big mantra is control, control in terms of where we put things [on the viral cage], how much we put on, and how and when we release it.”

A virus harnessed to deliver enough imaging agent to visualize even a small biofilm and at the same time deliver a drug to destroy it could usher in the demise of biofilms in the clinic.