Computational Design and Engineering of Metal Oxide Nanozymes

The average age of UK population is increasing and a rise in diseases related to accumulation of radical species in living cells, i.e. oxidative stress, is reported. To achieve a "Healthy Nation", there is therefore a need to develop cost-effective and high efficient nanotechnologies for prevention, diagnosis and therapy of diseases that are caused or can cause oxidative stress. Oxidative stress has been linked to degenerative diseases and cancer. Radicals are normally regulated by enzymes but when they accumulate, we need a technology that can control their concentration. Nanozymes can mimic enzyme activities and regulate the concentration of radicals in living cells. Thus, the importance of understanding and developing materials for nanozymes based technologies.

This computational project will use a combination of different modelling techniques to develop nanotechnologies based on metal oxide nanoparticles that are able to mimic enzyme activity towards the scavenging of radicals. As the enzyme-mimetic activities depends on the surface composition and reactivity of the metal oxide nanoparticles, it is important to gain insights at the nanoscale. Therefore, computational techniques based on both ab initio and classical methods will be used to gain information that is complementary to experimental findings.

This project is multidisciplinary as it brings together materials science and biomedicine through a research team of computational and experimental researchers. Advanced functional materials with enzyme-mimetic activity can regulate radicals in biological environments. These nanozymes, however not always present a simple enzyme-mimetic activity but rather they show a complex behaviour. This is due to their high reactivity at their surface.

We will focus our attention on nanoceria, a material that showed value as a protective agent for cellular aging, neurodegenerative disorders, cardiovascular pathologies, retinal degeneration, cancer treatment and tissue engineering. Nanoceria displays high surface reactivity and can mimic enzymes such as superoxide dismutase and catalase that regulate superoxide radicals and hydrogen peroxide, respectively. However, the exploitation of these two functions is altered by other surface activities such as the phosphatase activity and the adsorption of phosphates on nanoceria surfaces. Whereas experimental work is hindered by the complexity of the biological environments, computational work can attain information at the atom level and provide insights into the surface processes and reactivity. Therefore, this project will evaluate the surface composition and reactivity of nanoceria in the presence of biologically relevant oxyanions such as phosphates and identify the factors controlling nanoceria radical scavenging activity. We will then use these to generate guidelines to design and engineer nanoceria morphologies with enhanced enzyme-mimetic activities towards the scavenging of radicals. This will ultimately benefit the development of healthcare nanotechnologies based on the use of nanozymes.

This project is in line with the prosperity outcomes of the UK development plan 2016/17-2019/20 for the Healthy Nation ambitions "Optimisation of diagnosis and treatment", "Development of future therapeutic technologies", and "Transformation of community healthcare". These are also translated in the EPSRC Healthcare Technologies Grand Challenges.

The average age of UK population is increasing and a rise in diseases related to accumulation of radical species, i.e. oxidative stress, is reported. There is therefore a need for developing low cost and high efficient nanotechnologies for prevention, diagnosis and therapy of diseases that are caused or can cause oxidative stress. Nanozymes can mimic enzymes and regulate the concentration of radicals in living cells. The development of nanozymes based technologies will require the development of biocompatible advance functional materials and a full understanding of their surface catalytic properties. This can be translate into efficient sensing systems that can be implemented in cost-effective and reliable medical devices. Nanozymes can be implemented in immunoassays, logical monitoring gates, point-of-care testing (POCT) for diagnosis at the time and place of patient care rather than awaiting for medical laboratory analysis, as well as in future therapeutic technologies. Of course, their implementation in clinical practice will have to conform to the UK regulation and pass relevant clinical trials. Whereas this project will not deliver a functioning medical device, it will provide a computational procedure to determine and assess the enzyme mimetic activities of metal oxide nanoparticle as nanozymes. This procedure will be then developed in a large grant submission to EPSRC. As computational techniques are cheaper than in vitro and in vivo experimentation, the development of computational methodologies that can be routinely used will be cost-effective in the long term and if fully developed it will help avoiding the use of animals and human in clinical trials, which are always cause of growing ethical concern.

The results stemming from this project will make a key contribution to the UK's research leadership in materials for biomedical applications and to a broader extend to catalysis applications. The UK has a large investment in nanomaterials, with currently over 20 Micro and Nano Technologies (MNT) Centres, and the number of companies active in biological nanomaterials are second only to those active in the thin films and nanocoating. Involvement with the commercial and private sector will be embedded at several levels. Firstly, the University of Huddersfield Research and Enterprise team will provide support in the identification of intellectual properties and opportunities for commercial exploitation of research. Help will also be provided by Dr Seal who has extensive experience in patenting (over 60 patents). More feasible patents may include those on the design of nanozymes with enhanced enzyme mimetic activities. Secondly, the University of Huddersfield Business Development Team will support the development of industrial partnerships needed to the identification of opportunities to take the results further via further RCUK funding and applications in partnership with healthcare technologies companies via Innovate UK, e.g. via the KTP scheme were the University of Huddersfield has an excellent track record. This will bear the ultimate translation of research findings into real applications. To facilitate contact with the commercial sector, a workshop will also be held after the first 6 months of the project.