Engineering nanosponges to sequester bacterial exotoxins for protection against severe infection

Bacterial infections represent a significant challenge to clinicians and contribute substantially to healthcare costs worldwide. This challenge has been exacerbated by the rise in antimicrobial resistance which threatens to render current therapies obsolete. One such bacteria, Staphylococcus aureus, has been identified by the WHO as one of 10 priority pathogens which present the largest threat.

Antibiotic resistant strains (such as MRSA) have been associated with approximately 1 million deaths and were responsible for nearly 100,000 deaths in 2019 alone.

S. aureus infections can result in diverse symptoms ranging from more trivial superficial skin diseases to potentially fatal conditions such as bacteraemia, pneumonia and endocarditis. Importantly, S. aureus cells that invade host tissues use toxins secreted into the neighbouring environment that lead to cell damage and disease. The use of biomaterial-based technology to mimic host cells and thus to absorb these toxins offers a novel approach to tackling this issue.

By generating nanoparticles that are coated with immune cell membranes, these biomaterial particles could act as sponges and alleviate the deleterious impact of these bacterial toxins.

The main aims of the project are 1) to develop biomaterial-core nanoparticles and fuse with isolated white blood cell membranes to engineer nanosponges, 2) to evaluate nanosponge function against S. aureus toxins using a range of microbiological assays and techniques, and 3) to examine nanosponge efficacy against S. aureus infection using the Manduca sexta caterpillar as an in vivo model. Overall, the project aims to deliver a nanosponge-based approach to treating S. aureus infection from development stage through to in silica testing in cell-culture and in vivo evaluation in an invertebrate model. The chief objective is provide proof of concept for future research.

There is a plethora of potential applications of nanosponges, both within and outside the microbial arena. Chiefly, the ability for nanosponges to alleviate host infection and allow for an increased host immune response might lessen the need for clinicians to provide antibiotic treatments. In the case of the MRSA, the clinical use of nanosponge technology could - alongside conventional antimicrobial therapies - greatly aid in patient survival.

Furthermore, for milder cases the use of nanosponges alone might be enough to halt the infection, thus negating any use of antibiotics at all. By reducing reliance on antibiotics more widely, clinical use of nanosponge technology could also reduce the risk of future resistant bacterial strains.

Wider applications of nanosponge technology might involve their use as part of anti-cancer treatments. Biomaterial nanoparticles can be loaded with chemotherapy drugs and their cell membrane coating used to target particular cancer cells. They also offer potential as novel nanovaccines, the cell membrane potentially being able to present multiple antigens simultaneously to promote a host immune response.

The project described above has the utmost relevance to the EPSRC as it meets several EPSRC strategic priorities such as 'frontiers in engineering and technology' and 'transforming health and healthcare', as well as fitting with MRC and wider UKRI priorities involving 'infectious human diseases' and 'the fight against infections and antimicrobial resistance'.