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

非技术摘要：自然杀伤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，在体内稳定，并含有抗病毒成分。因此，研究NKE的材料特性对于设计合成的仿生纳米颗粒至关重要，这些纳米颗粒可以扩大规模用于抗病毒应用，包括COVID-19。为了满足这些需求，生物材料计划的EAGER奖的总体目标是研究NKE的纳米材料特性，膜成分和货物。利用这些新知识，PI和她的实验室将测试这些材料特性如何影响膜融合，以及细胞内化和抗SARS-CoV-2感染的抗病毒功能。由于发现NK细胞活性在不同患者人群中存在差异，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，并可用于获得对药物递送系统的相容性、稳定性和整体性能至关重要的新知识。这些研究工作将与K-12，本科生和研究生以及公众的教育和宣传活动相结合。在大学和研究生层面的活动集中在招聘，指导和培训妇女，URM，和LGBTQ学生通过深入的研究经验，而K-12活动是基于课堂讲座和动手演示。此外，PI将通过与加州科学中心的合作以及K-12学生的社交媒体平台与公众互动。我们的目标是激励、吸引和培养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：自然杀伤（NK）细胞是抵御病毒感染的第一道防线，有助于消除不健康的宿主细胞。尽管NK细胞已被提议作为针对由病毒感染（诸如COVID-19）引起的疾病的基于细胞的疗法，但细胞疗法具有挑战，包括有限的细胞体内存活、短的保质期和高成本。相反，赋予NK细胞自然杀伤特性的细胞毒性细胞外囊泡（EV）具有作为长期现成药物递送载体扩大规模的潜力，并且可以用于为抗病毒应用提供稳定的仿生药物递送载体的设计。为此，PI和她的实验室将首先1）表征来自几个人类来源的NK EV（NKE）的材料特性以及脂质、蛋白质和RNA膜和货物组成。然后，PI和她的实验室将2）在感染SARS-CoV-2的细胞中评估NKE细胞内化和抗病毒活性，并评估NKE组成和材料特性的差异如何影响它们的功能。该研究计划的成功预计将推进NKE的基础知识，并阐明其与抗病毒功能相关的材料特性。因此，在当前的大流行（例如COVID-19）期间，研究提案的结果可能对评估NKE作为抗病毒治疗的新来源具有重要意义，但对其他病毒感染的免疫治疗具有潜在益处。研究计划与教育和推广计划相结合，其中包括：1）通过深入的研究经验招募，培训和指导来自不同背景的本科生和研究生，包括女性，URM和LGBTQ团体，2）关于生物纳米材料的课堂讲座和实践活动，包括最近COVID-19疫苗中的纳米颗粒载体（第32街学校，洛杉矶联合学区），和3）纳米日，一个年度计划，将包括生物纳米技术演示在加州科学中心，和NanoPeek，我们的社会媒体平台，展示生物纳米技术的内容。总之，这些举措旨在激发，参与和传播知识，以不同的观众，从K-12到公众，关于医学中的生物纳米材料及其解决全球公共卫生问题的潜力，如流行病。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

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.