EAGER: Carbon Dot-Based Transformative COVID-19 Therapy

冠状病毒病2019(新冠肺炎)是由新型冠状病毒(SARS-CoV-2)引起的。这种疾病是一个关系到每个人的健康和安全的严重问题。截至2020年7月15日，它已在全球造成超过58万人死亡，预计在不久的将来还会复发。目前，新冠肺炎无法治愈，传统化疗面临一系列挑战，包括：(1)SARS-CoV-2病毒容易变异的能力；(2)无效抗体；(3)大多数治疗剂无法跨越血脑屏障。因此，这些因素的结合使SARS-CoV-2有机会隐藏在大脑中，当人体的免疫系统变得虚弱时，它会复制并对人体构成挥之不去的威胁。因此，利用生物医学工程的手段来预防病毒进入具有重要意义。在这个项目中，碳点，一种可以穿越血脑屏障的新型纳米颗粒，将被用作各种抗体的多功能纳米载体，以及一种已被用于治疗新冠肺炎的抗病毒药物瑞希韦。这种方法将利用由专门的宿主细胞和病毒组成的模型来模拟SARS-CoV-2的感染过程。该项目的结果可能会导致研究，在这些研究中，可以使用纳米颗粒和治疗剂来治疗大量的病毒疾病，使用这项工作中介绍的方法。在教育方面，该项目将为本科生和研究生提供一系列研究方法的培训经验，包括表面化学、光谱学、纳米材料、生物分析、纳米载体和生物纳米技术。外联活动包括与媒体和电视合作宣传科学技术，与迈阿密弗罗斯特科学博物馆合作策划展品并向普通公众宣传科学。本研究项目的目标是设计一种新型的生物医学系统，将碳点(Cd)用作治疗性纳米载体。这些碳点将与SARS-CoV-2刺突蛋白抗体(CD-NABS)、宿主细胞血管紧张素转换酶2受体抗体(CD-BABS)和瑞希韦偶联。将开发一种由伪宿主细胞和伪病毒组成的新的疾病模型来分析碳点结合物的抑制效果。我们将通过测量碳点抗体结合物的IC50来比较单独和联合给药的效果。研究思路是CD-NABS和CD-BABS分别与伪病毒和伪宿主细胞相互作用。碳点偶联物的存在会通过空间位阻效应和静电斥力减少SARS-CoV-2与宿主细胞表面的结合。在ACE2 BABS的帮助下，碳点结合物将能够将雷米希韦输送到受感染的细胞中，以防止病毒复制。这一研究项目的结果有望为碳点结合物是否以及在多长时间内通过减少其可用的结合位点和抑制病毒进入细胞而阻止SARS-CoV-2感染宿主细胞提供基本见解。这一奖项反映了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。

Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus (SARS-CoV-2). This disease is a critical problem that concerns everyone’s health and safety. As of July 15th, 2020, it has caused more than 580,000 deaths worldwide, and it is predicted to recur in the near future. At this time there is no cure to COVID-19 and traditional chemotherapy faces a series of challenges including: (1) the ability of SARS-CoV-2 to mutate readily; (2) ineffective antibodies; and (3) inadmissibility of most therapeutic agents across the blood-brain barrier. Consequently, this combination of factors gives SARS-CoV-2 an opportunity to hide in the brain, replicating and posing a lingering threat to the human body when its immune system becomes weak. Therefore, it is of great importance to come up with a treatment using the tools of biomedical engineering to prevent viral entry. In this project carbon dots, a class of novel nanoparticles that can cross the blood-brain barrier, will be utilized as versatile nanocarriers for various antibodies and an antiviral drug, remdesivir, that has been used to treat COVID-19. This method will make use of models comprised of specialized host cells and viruses to simulate the infection process of SARS-CoV-2. The outcomes of this project could lead to studies in which a great number of viral diseases can be treated with nanoparticles and therapeutic agents using the methodology introduced in this work. On the educational front, the project will provide training experiences for undergraduate and graduate students in a range of research methods, including surface chemistry, spectroscopy, nanomaterials, bioanalysis, nanocarriers, and bionanotechnology. Outreach activities include working with the media and TV to promote science and technology and participating with the Miami Frost Science Museum to curate exhibits and promote science to the general public. The goal of this research project is to design a novel biomedical system that applies carbon dots (CDs) as therapeutic nanocarriers. The carbon dots will be conjugated with antibodies of the spike proteins on SARS-CoV-2 (CD-NAbs), antibodies of the angiotensin-converting enzyme 2 (ACE2) receptors on host cells (CD-BAbs), and remdesivir. A novel disease model comprised of pseudohost cells and pseudoviruses will be developed used to analyze the inhibition effectiveness of the carbon dot conjugates. The effectiveness of separate and combined delivery of the carbon dot-antibody conjugates will be compared by measuring their IC50. The research idea is that CD-NAbs and CD-BAbs can respectively interact with the pseudoviruses and the pseudohost cells. The presence of carbon dot conjugates will reduce the binding of SARS-CoV-2 to the surface of host cells by steric effects and electrostatic repulsive forces. With the help of ACE2 BAbs, carbon dot conjugates will be able to deliver remdesivir into the infected cells to prevent viral replication. The results from this research project are expected to provide fundamental insights into whether and how long carbon dot conjugates will keep SARS-CoV-2 from infecting the host cells by reducing their available binding sites and inhibiting the approach of the virus to the cells.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.