In 1956, Nobel Prize winning physicist Richard Feynman gave a lecture at the California Institute of Technology hypothesizing on our ability to engineer and manipulate material at the atomic scale. Here, he even suggested the possibility of building nanoscale surgical robots. These ideas – collectively describing the design, manipulation, application and production of materials, particles and systems in the range of 1 to 100nm – were termed nanotechnology in 1974 by scientist Norio Taniguchi. In reality, however, nanotechnology has been employed since the 4th century, when gold, silver, copper and other metal nanoparticles were made to obtain the exquisite optical properties seen in dichroic glass, ceramic glazes and stained glass windows. Today, nanoparticles are knowingly at play in many aspects of science and technology.

What makes nanoparticles so unique is the fact that materials have very different properties when their size is reduced to the nanometre range. When miniaturized, the surface to volume ratio of particles is increased tremendously, such that most of the molecules that make up the unit are in contact with the environment rather than with each other. Importantly for biology, this endows the material with different physicochemical properties and enhances their interaction with the biological environment. Furthermore,  nanoparticles are on the same scale as viruses and the molecular complexes that regulate cells. Thus, tuning a nanoparticle’s magnetic, optical and chemical properties gives scientists the opportunity to experiment with and direct desired functions in cellular systems in a minimally invasive fashion. Because of this capacity for precision, the Food and Drug Administration (FDA) has already approved nanomaterials for use in a wide variety of biomedical applications, including iron oxide nanoparticles as MRI contrast agents, gold nanoparticles for in vitro diagnostics, and protein nanoparticles for cancer treatment.

Nanotechnology and Immunology
In the field of immunology, nanotechnology enables a new level of immune-modulation. Although not widely recognized as a nanotechnology application, one of the first approaches involved the generation of new and improved vaccines. While vaccines have been used for decades to prevent infectious diseases, there are still many cases where vaccination has not been successful due to the inability of subunit vaccines to elicit a strong enough immune response or fears of an attenuated viral vaccine reverting to the pathogenic state. The use of nanoparticles offers a way to simulate the effect of attenuated vaccines synthetically, thus eliminating the risk of infection. Importantly, the small nature of the particles allows them to migrate to the lymph nodes, the site of action for generating an immune response. The first nanoparticle vaccine was the Hepatitis B Virus (HBV) vaccine, created in 1981 when scientists discovered that nanoparticles composed of an HBV core protein isolated from infected patients were highly immunogenic. Almost three decades later, two other nanoparticle vaccines, Gardasil and Cervarix, demonstrated efficacy in generating an immune response against Human Papilloma Virus (HPV). All of these nanoparticles are termed viral-like particles (VLP), as they try to recapitulate the “shell” of the virus with a particular core protein while also encapsulating adjuvant within it. This system mimics the repetitive structure the protein would have if it were on the actual virus, and allows for the combined release of adjuvant and antigen to ensure timely activation of antigen presenting cells. This concept has recently been applied to produce a vaccine against malaria by combining the HBV core protein antigen with the malaria circumsporozoite antigen (CSP), which so far has shown up to 50% efficacy in children in Africa. Several other systems  are also showing promising results for improved vaccine production. For example, lipid nanoparticles (LNP) can be used as DNA/RNA carriers since they protect the nucleotides from degradation, allow fusion with membranes and can be decorated with specific receptors to target delivery to desired cells.

Besides their utility in vaccine production, nanoparticles are being used in many creative ways to enhance immune responses. Artificial antigen presenting cells have been generated by covering the surface of nanoparticles with major histocompatibility complex and co-receptor molecules, while loading the inside of the particle with co-stimulatory cytokines. When cultured with T cells, these nanoparticles were able to efficiently activate the cells and locally deliver the cytokine IL-2, allowing for enhanced activation of specific cell populations. The migratory nature of immune cells is also being used to deliver nanoparticles to places such as tumours that are hard to reach with normal therapeutics. For example, nanoparticles containing gold nanoshells have been purposely designed to get phagocytosed by macrophages, which lead nanoparticles to the tumours and and trap them there. When irradiated with near-infrared light, these nanoparticles heat and lyse the macrophages that engulfed them. This damages the surrounding microenvironment, which includes by-stander tumour cells, thus contributing to the anti-tumorigenic effect. In other cases, such as for drug delivery, phagocytosis of the nanoparticle is not the desired goal.  Luckily, altering the size and shape of nanoparticles changes their cellular interactions and enables a level of control over their sequestration, engulfment, and biodistribution.

Nanoparticles are also great tools for exploring the basic concepts of receptor signalling in cells. Cell signalling is subject to many physical, chemical, spatial and temporal cues that are generally hard to manipulate. Nanoparticles have been created that can induce all of these cues on cell surface receptors, allowing researchers to figure out which of these parameters are actually important for cell activation.

The Dark Side of Nanoparticles
Although nanotechnology is revolutionizing many aspects of science and technology, it does have some downsides. Nanoparticles are often engineered from non-organic materials that do not biodegrade and consequently can induce a number of toxic side effects in both their host and the environment. For example, zinc-oxide nanoparticles used in sunscreen agents have been shown to accumulate in the tissues of plants and prevent nitrogen fixation. Metal nanoparticles, which can be derived naturally from metallic implants, jewelry or metal wires, have been linked to allergic reactions. Gold, a material that is very appealing for cancer treatment, chronically accumulates in the liver and spleen and imparts a metallic burden that limits the number of times an animal may be exposed to the nanoparticle formulation. For these reasons, there is a big demand in the field for longer-term toxicity studies to evaluate the impact of materials on the body, as well as for more organic-based reagents so that nanoparticles will be biodegradable and safer to use.

Nanotech at the University of Toronto

James Lazarovits (left) and Yih Yang Chen (right), Dr. Warren Chan’s lab, Institute of Biomaterials and Biomedical Engineering, University of Toronto. Photo credit: Mayra Cruz Tleugaboulova.
James Lazarovits (left) and Yih Yang Chen (right), Dr. Warren Chan’s lab, Institute of Biomaterials and Biomedical Engineering, University of Toronto. Photo credit: Mayra Cruz Tleugaboulova.

At the University of Toronto, the lab of Dr. Warren Chan is making big strides in understanding the interactions between nanoparticles and biological systems. Rather than looking at how nanoparticles change the body, his lab is working towards understanding how the body modifies materials in order to tailor nanoparticles to the natural ways the body responds to them. As the particles go through the body, their shape, size and surface chemistry is modified by their interactions with the cells and proteins that they encounter. “Nanoparticles that can effectively localize to a stage I tumour might not interact the same way to a stage IV tumour,” indicates James Lazarovits, a graduate student in Chan’s lab, “and understanding why this happens is necessary in order to use the appropriate material.” For this reason, the lab is carefully characterizing the interactions of nanoparticles with cells and vasculature in the liver, an organ where nanoparticles tend to localize. They also study how nanoparticles can be guided to sites of interest in cancer treatment, and so far, they have found that a core size of 50nm is best for localizing nanoparticles to tumours while minimizing off-target organ accumulation. Using knowledge gained from these studies, Chan’s lab is now creating nanoparticle tools that can be used as diagnostic and therapeutic agents. For example, the team has generated nanoparticles that can be controlled through interactions with specific sequences of DNA, such that a ligand on the nanoparticle that targets a particular cellular receptor is only exposed in the presence of a certain DNA code. Their future studies aim to tackle new creative ways to use materials for biomedical applications.
Conclusion
From its initial conception, nanotechnology has changed much of the way we think about the application of biomedical therapies. The field is continuously expanding, with the Institute of Biomaterials and Biomedical Engineering at the University of Toronto recruiting new faculty members to explore more of these concepts. With more advances, Feynman’s vision of a nanoscale surgeon might not be so far down the line.


References

1. Gomes A et al. Harnessing Nanoparticles for Immunomodulation and VaccinesVaccines, 5(1), pii: E6. doi: 10.3390/vaccines5010006 (2017).
2. Interview with James Lazarovits and Yih Yang Chen, Warren Chan’s lab, Instituteof Biomaterials and Biomedical Engineering, University of Toronto.
3. Kim BYS et al. NanomedicineN Engl J Med, 363(25):2434–2443 (2010).
4. Moon J et al. Engineering Nano‐ and Microparticles to Tune ImmunityAdvanced Materials, 24(28): 3724–3746 (2012).
5. Parak, WJ. Controlled interaction of nanoparticles with cellsScience 351(6275):814–815 (2016).
6. Seo D et al. A Mechanogenetic Toolkit for Interrogating Cell Signaling in Space and TimeCell, 165(6): 1507–1518 (2016).
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Mayra Cruz Tleugabulova

Mayra is a doctoral student in the department of Immunology at the University of Toronto. She's currently studying basic aspects of the development and function of Natural Killer T cells.

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