Engineering nanosponges to sequester bacterial exotoxins for protection against severe infection

细菌感染对临床医生来说是一个重大挑战，并在全球范围内大大增加了医疗成本。抗菌素耐药性的上升加剧了这一挑战，这有可能使目前的治疗方法过时。其中一种细菌，金黄色葡萄球菌，已被世卫组织确定为构成最大威胁的10种重点病原体之一。抗生素耐药菌株（如MRSA）与大约100万人的死亡有关，仅在2019年就造成近10万人死亡。金黄色葡萄球菌感染可导致多种症状，从比较轻微的浅表皮肤病到可能致命的疾病，如菌血症、肺炎和心内膜炎。重要的是，入侵宿主组织的金黄色葡萄球菌细胞使用分泌到邻近环境的毒素，导致细胞损伤和疾病。利用基于生物材料的技术来模拟宿主细胞，从而吸收这些毒素，为解决这一问题提供了一种新的方法。通过产生包裹着免疫细胞膜的纳米颗粒，这些生物材料颗粒可以起到海绵的作用，减轻这些细菌毒素的有害影响。该项目的主要目标是1)开发生物材料核心纳米颗粒并与分离的白细胞膜融合以设计纳米海绵，2)使用一系列微生物分析和技术评估纳米海绵对金黄色葡萄球菌毒素的功能，以及3)使用Manduca sexta毛虫作为体内模型检查纳米海绵对金黄色葡萄球菌感染的功效。总的来说，该项目旨在提供一种基于纳米海绵的方法来治疗金黄色葡萄球菌感染，从开发阶段到细胞培养的二氧化硅测试和无脊椎动物模型的体内评估。主要目的是为未来的研究提供概念证明。纳米海绵在微生物领域内外都有大量的潜在应用。首先，纳米海绵减轻宿主感染和增强宿主免疫反应的能力可能会减少临床医生提供抗生素治疗的需要。就MRSA而言，纳米海绵技术的临床应用——与传统的抗微生物疗法一起——可以极大地帮助患者生存。此外，对于病情较轻的病例，仅使用纳米海绵可能就足以阻止感染，从而完全不需要使用抗生素。通过更广泛地减少对抗生素的依赖，纳米海绵技术的临床应用也可以降低未来耐药细菌菌株的风险。纳米海绵技术的更广泛应用可能包括将其用作抗癌治疗的一部分。生物材料纳米颗粒可以装载化疗药物和它们的细胞膜涂层，用于靶向特定的癌细胞。它们还提供了作为新型纳米疫苗的潜力，这种细胞膜可能能够同时呈递多种抗原，以促进宿主的免疫反应。上述项目与EPSRC有最大的相关性，因为它符合EPSRC的几个战略优先事项，如“工程和技术前沿”和“转变健康和医疗保健”，以及与MRC和更广泛的UKRI优先事项相匹配，包括“人类传染病”和“对抗感染和抗菌素耐药性”。

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'.