EAGER-Harnessing natural killer cell-derived extracellular vesicles as anti-viral nanomaterials

EAGER-利用自然杀伤细胞来源的细胞外囊泡作为抗病毒纳米材料

• 批准号: 2132744
• 负责人: Eun Ji Chung
• 金额: $ 14.46万
• 依托单位: University of Southern California
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2132744&HistoricalAwards=false
• 关键词: EAGER; Harnessing; natural; killer; cell

NON-TECHNICAL ABSTRACT:Natural killer cell-derived extracellular vesicles (NKE) are natural nanoparticles that are inherently biocompatible, stable in vivo, and contain anti-viral components. As such, investigating the materials properties of NKE will be critical to informing the design of synthetic, biomimetic nanoparticles that can be scaled-up for anti-viral application including COVID-19. To meet these needs, the overall goal of this EAGER award by the Biomaterials Program is to study the nanomaterial properties, membrane composition, and cargo of NKE. Using this new knowledge, the PI and her lab will test how these material properties affect membrane fusion, as well as cell internalization and anti-viral function against SARS-CoV-2 infection. Since NK cell activity has been found to differ among various patient populations, the PI will also elucidate how the materials properties of extracellular vesicles vary with biological factors, and can be used to obtain new knowledge that is critical for compatibility, stability, and overall performance of drug delivery systems. These research efforts will be integrated with education and outreach initiatives for K-12, undergraduate, and graduate students and for the public. The activities at the college and graduate levels are centered on recruitment, mentorship, and training women, URM, and LGBTQ students through in-depth research experiences, while K-12 activities are based on classroom lectures and hands-on demos. In addition, the PI will interact with the public through an established collaboration with the California Science Center and a social media platform for K-12 students. The goal is to inspire, engage, and prepare the next generation of scientists and engineers from diverse backgrounds to develop innovative solutions that can benefit global public health.TECHNICAL ABSTRACT:Natural killer (NK) cells are the first line of defense against viral infections and helps eliminate unhealthy host cells. Although NK cells have been proposed as a cell-based therapy against diseases caused by viral infections such as COVID-19, cell therapy has challenges including limited cell survival in vivo, short shelf-life, and high cost. Instead, the cytotoxic, extracellular vesicles (EVs) that endow natural killing properties to NK cells have the potential to be scaled-up as long-term, off-the-shelf drug delivery carriers and can be used to inform the design of stable, biomimetic drug delivery carriers for anti-viral application. To that end, the PI and her lab will first 1) characterize the material properties, as well as lipid, protein, and RNA membrane and cargo composition of NK EVs (NKE) originating from several human sources. Then, the PI and her lab will 2) evaluate NKE cell internalization and anti-viral activity in cells infected with SARS-CoV-2 and assess how differences in NKE composition and materials properties influences their function. Success of the research plan is anticipated to advance fundamental knowledge of NKE, and elucidate their material properties as it relates to anti-viral function. Thus, the results from the research proposal may be significant during the current pandemic (e.g. COVID-19) in evaluating NKE as a novel source of anti-viral therapy, but will have potential benefits for immunotherapy in other viral infections. The research plan is integrated with the education and outreach plan which includes: 1) recruitment, training, and mentoring of undergraduate and graduate students from diverse backgrounds including women, URM, and LGBTQ groups through in-depth research experiences, 2) classroom lecture and hands-on activities regarding bio-nanomaterials including nanoparticle carriers in recent COVID-19 vaccines (32nd Street School, Los Angeles Unified School District), and 3) NanoDays, an annual program that will include bio-nanotechnology demos at the California Science Center, and NanoPeek, our social media platform that showcases bio-nanotechnology content. Together, these initiatives aim to excite, engage, and disseminate knowledge to a diverse audience ranging from K-12 to the public regarding bionanomaterials in medicine and its potential to solve global public health issues such as pandemics. The effectiveness of the programs will be evaluated for each activity.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.

非技术摘要：天然杀手细胞衍生的细胞外囊泡（NKE）是天然纳米颗粒，具有固有的生物相容性，体内稳定并包含抗病毒成分。因此，研究NKE的材料特性对于通知合成，仿生纳米颗粒的设计至关重要，这些纳米颗粒可以用于包括Covid-19的抗病毒应用。为了满足这些需求，生物材料计划渴望奖励的总体目标是研究NKE的纳米材料，膜成分和货物。使用这些新知识，PI和她的实验室将测试这些物质特性如何影响膜融合，以及针对SARS-COV-2感染的细胞内在化和抗病毒功能。由于已经发现NK细胞活性在各个患者种群之间有所不同，因此PI还将阐明细胞外囊泡的材料特性如何随生物因素而变化，并可用于获得对兼容性，稳定性和药物输送系统整体性能至关重要的新知识。这些研究工作将与K-12，本科和研究生以及公众的教育和外展计划融合。学院和研究生级别的活动集中在招聘，指导和培训女性，URM和LGBTQ学生通过深入的研究经验，而K-12活动基于课堂讲座和动手演示。此外，PI将通过与加利福尼亚科学中心的既定合作和K-12学生的社交媒体平台与公众互动。目的是激励，参与和准备来自不同背景的下一代科学家和工程师，以开发有益于全球公共卫生的创新解决方案。技术摘要：自然杀手（NK）细胞是针对病毒感染的第一道防线，并有助于消除不健康的宿主细胞。尽管已提出了NK细胞作为对病毒感染（例如Covid-19）引起的疾病的基于细胞的疗法，但细胞疗法的挑战包括在体内，短暂的保质期和高成本中的细胞存活率有限。取而代之的是，赋予NK细胞的自然杀伤特性的细胞毒性，细胞外囊泡（EV）具有长期，现成的药物递送载体的可能性，可用于为抗病毒申请的稳定，仿生药物递送载体的设计提供信息。为此，PI和她的实验室将首先1）表征材料特性，以及来自几种人类来源的NK EVS（NKE）的脂质，蛋白质和RNA膜和货物组成。然后，PI和她的实验室将2）评估感染SARS-COV-2的细胞中NKE细胞内在化和抗病毒活性，并评估NKE组成和材料特性的差异如何影响其功能。预计研究计划的成功将促进NKE的基本知识，并在与抗病毒功能有关的情况下阐明其物质特性。因此，研究建议的结果在当前大流行期间（例如Covid-19）在评估NKE作为抗病毒疗法的新来源时可能很重要，但在其他病毒感染中将具有免疫疗法的潜在益处。 The research plan is integrated with the education and outreach plan which includes: 1) recruitment, training, and mentoring of undergraduate and graduate students from diverse backgrounds including women, URM, and LGBTQ groups through in-depth research experiences, 2) classroom lecture and hands-on activities regarding bio-nanomaterials including nanoparticle carriers in recent COVID-19 vaccines (32nd Street School, Los Angeles Unified School区域）和3）Nanodays是一项年度计划，其中包括加利福尼亚科学中心的生物纳米技术演示以及我们的社交媒体平台Nanopeek，它展示了生物纳米技术内容。这些举措共同旨在激发，吸引和传播知识，向从K-12到公众关于医学中的bionanomamaterials及其解决全球公共卫生问题（如大流行）的潜力。该计划将对每项活动进行评估。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响审查标准，被认为值得通过评估获得支持。