EAGER: Bioengineered Nanobarrier to Protect Against SARS-Cov-2 and Other Viral Infections of the Nasopharynx

2019年冠状病毒病(新冠肺炎)大流行极大地影响了人类的生活方式，已导致全球600多万人死亡。该项目使用局部屏障来增强鼻腔衬里的防御能力，这是防止严重急性呼吸综合征冠状病毒2(SARS CoV-2)感染的一种非常新颖的方法。这个早期概念的探索性研究拨款(AGER)项目的目的是设计一种鼻喷剂和新型喷雾器，这种喷雾器可以提供一种特殊的涂层，防止病毒和微生物感染。这种用户友好的方法，如果进一步发展，有可能有效地防止SAR-CoV-2变种感染人类。此外，这种创新的屏障可以降低其他空气传播威胁的风险，例如，可以在流感季节或新出现的大流行期间迅速使用。所开发的计算机计算模型也可用于加快制定准确和精确的对策。计划中的研究将提供机会，培养通过高度跨学科(工程学、分子生物学、病毒学和药理学)研究进行合作的工程学和生物医学学生，并将加强持续的教育和外展活动，重点是吸引代表不足的少数群体进入这些研究领域。该项目的总体目标是设计一种创新的、可生物降解的纳米屏障(抗病毒涂层)，它是安全的，可以广泛部署，以保护公众免受SARS-CoV-2感染。尽管疫苗、口罩强制要求和社交距离等传统方法正在被用来预防或减少新冠肺炎的传播，但长期合规是一个挑战。因此，迫切需要一种新的感染预防方法。该项目提出了一种用户友好的纳米屏障，旨在通过增强鼻咽通道中发现的粘膜皮肤衬里的防御能力来防止病毒和微生物附着和感染上皮细胞。纳米载体通过隔离病毒附着、感染和传播所需的基本胆固醇来灭活被包裹的病毒。该项目有两个主要目标：(1)利用鼻咽腔的三维模拟来优化参数(水滴和递送产品的特性)，以指导工程应用设备的设计，将纳米屏障准确地沉积到新冠肺炎感染最敏感的区域，从而便于转化为临床前模型；以及(2)评估纳米屏障在经验证的冠状病毒小鼠模型中的疗效。最终的纳米屏障将不受SARS-CoV-2变种的影响，可以迅速推出，有效地防止感染。这个项目中使用的模拟方法将作为一个平台，开发具有针对性的干预措施，并将其最优化地输送到鼻咽腔。此外，该项目将扩大对SARS-CoV-2变种如何感染以及它们的易感性的知识和理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The Coronavirus Disease 2019 (COVID-19) pandemic has dramatically impacted the way humans live and has resulted in more than 6 million deaths worldwide. This project uses a topical barrier to enhance the defense capabilities of the lining found in the nose, which is a highly novel method to prevent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) infections. The aim of this EArly-concept Grant for Exploratory Research (EAGER) project is to engineer a nasal spray and new type of applicator that can deliver a special coating that prevents viral and microbial infection. This user-friendly approach, if further developed, has the potential to be effective in preventing SAR-CoV-2 variants from infecting humans. Moreover, the innovative barrier could reduce the risk of other airborne threats, e.g., could be rapidly employed during the flu seasons or new emerging pandemics. The in silico computational models developed can also be used to expedite the development of accurate and precise countermeasures. The planned studies will provide opportunities to train engineering and biomedical science students who work collaboratively through highly interdisciplinary (engineering, molecular biology, virology and pharmacology) research studies and will enhance ongoing education and outreach activities focused on attracting underrepresented minority groups into these areas of research.The overall goal of this project is to engineer an innovative, biodegradable, nanobarrier (anti viral coating) that is safe and can be widely deployed to protect the public from SARS-CoV-2 infections. Although traditional approaches like vaccines, mask mandates, and social distancing are being used to prevent or reduce the spread of COVID-19, long-term compliance is a challenge. Therefore, a novel approach to infection prevention is urgently needed. This project proposes a user-friendly nanobarrier designed to prevent viral and microbial attachment and infection of epithelial cells by enhancing the defense capabilities of the mucocutaneous lining found in nasopharyngeal passages. The nanobarrier inactivates enveloped viruses by sequestering essential cholesterols required for viral attachment, infection, and transmission. This project has two major objectives: (1) to use 3D-simulation of the nasopharyngeal cavity to optimize the parameters (droplet and delivery product characteristics) to guide the engineering of an applicator for accurate deposition of the nanobarrier to areas most susceptible to COVID-19 infection, facilitating translation into preclinical models, and (2) evaluate the efficacy of the nanobarrier in a validated coronavirus mouse model. The final nanobarrier will be agnostic to SARS-CoV-2 variants and can be quickly rolled-out to effectively prevent infection. The simulation approach used in this project will serve as a platform to develop targeted interventions with optimized delivery into the nasopharyngeal cavity. Additionally, this project will expand knowledge and understanding of how SARS-CoV-2 variants infect as well as their susceptibility.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.