CAREER: Revealing the fundamental interactions of cell-penetrating nanoparticles in a complex model membrane

该职业奖支持一项变革性的研究和教育计划，以了解新型纳米颗粒如何以被动和看似无损的方式穿透细胞膜。揭示这些细节将释放出在生物医学和农业中开发有用的细胞渗透剂的巨大潜力，并使我们能够更好地识别纳米材料的安全性。为了为持久的科学贡献奠定基础，该研究项目将利用首席研究员开创的新方法来组装和表征复杂的模型膜，以更好地模拟细胞中发现的那些膜。这项研究将产生关于纳米颗粒表面的化学和图案化如何使其在细胞中被吸收的新知识，这将直接有利于新一代纳米材料的设计、测试和使用。与研究项目密切相关的是一个名为INTERFACE的教育和推广计划，它将使更多的人参与到PI的实验室中产生的研究和技术中，并与之互动。界面包括关于生物活性纳米颗粒的性质和背景的公共论坛，为K-12和本科生开展的动手研究活动，以及支持以STEM为重点的新闻报道和改进的科学交流活动。这些活动通过激发人们对STEM的兴趣、教育公众、改善科学新闻、增加未被充分代表的群体的参与以及丰富工程学课程来支持更广泛的影响。这个职业奖支持一个变革性的研究和教育计划，以了解新型的两亲性单层保护的纳米颗粒如何被动地、似乎是非破坏性地穿透细胞膜。揭示这些机制将释放细胞渗透剂在生物医学中的巨大潜力，并使我们能够更好地识别纳米材料的安全性。为了为持久的贡献奠定基础，拟议的项目将利用PI开创的新方法组装复杂的脂双层，更好地模拟细胞内的膜，并原位表征其结构和运输性质。该研究项目旨在：1)开发用于操作、表征和成像复杂模型膜的变革性工具；2)量化两亲性纳米颗粒对膜结构的吸附、插入和移位的影响；3)揭示脂质类型和热致相对纳米颗粒活性的影响；以及4)考察纳米颗粒对膜中横向组织的反向影响。通过将两亲性纳米颗粒的活性与膜电容、厚度、张力、膜内电位、电导和多肽的侧向组织联系起来，清楚地了解两亲性纳米颗粒是如何穿透膜的，这一智能优势来自于所述的目标和预期结果。通过研究可以组装成模拟各种细胞的同质和非均质膜，这项工作将产生关于哪些脂类结构域更受欢迎的新信息，并测试两亲纳米颗粒更喜欢缺陷、高曲率区域和胆固醇贫乏区域的假设。与这项研究密切相关的是一个名为INTERFACE的教育和推广计划，它将使更多的人能够参与主要研究人员实验室产生的研究和技术并与之互动，这是该项目的结果。INTERFACE包括关于生物活性纳米颗粒的性质和背景的公共论坛，面向K-12和本科生的动手研究活动，以及支持以STEM为重点的新闻和改进的科学交流活动。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。

This CAREER award supports a transformative research and education program to understand how novel types of nano-scale particles penetrate cellular membranes in a passive and seemingly nondestructive manner. Revealing these details will unlock tremendous potential for developing useful cell penetrating agents in biomedicine and agriculture and enable us to better discern the safety of nanomaterials. To lay a foundation for lasting scientific contributions, the research project will leverage new methods pioneered by the Principal Investigator to assemble and characterize complex model membranes that better mimic those found in cells. This research will generate new knowledge of how the chemistry and patterning of nanoparticle surfaces enable their uptake in cells, which will directly benefit the design, testing, and use of new generations of nanomaterials. Closely tied to the research project, an educational and outreach program entitled INTERFACE will enable a wider range of people to engage in and interact with the research and technologies produced in the PI's lab as a result of this project. INTERFACE includes public forums on the nature and context of bio-active nanoparticles, hands-on research activities for K-12 and undergraduate students, and support for STEM-focused journalism and improved science communication activities. These activities support broader impacts by generating interest in STEM, educating the public, improving scientific journalism, increasing participation of underrepresented groups, and enriching engineering curricula.This CAREER award supports a transformative research and education program to understand how novel types of amphiphilic monolayer-protected nanoparticles passively, and seemingly nondestructively, penetrate cellular membranes. Revealing these mechanisms will unlock tremendous potential for cell penetrating agents in biomedicine and enable us to better discern the safety of nanomaterials. To lay a foundation for lasting contributions, the proposed project will leverage new methods pioneered by the PI to assemble complex lipid bilayers that better mimic membranes in cells and characterize in situ both their structural and transport properties. The research project seeks to: 1) develop transformative tools for manipulating, characterizing, and imaging complex model membranes; 2) quantify the effects of amphiphilic nanoparticle adsorption, insertion, and translocation on membrane structure; 3) uncover the effects of lipid type and thermotropic phase on nanoparticle activity; and 4) examine converse effects of nanoparticles on lateral organization in membranes. The intellectual merit stems from the stated objectives and expected outcomes to clearly understand how amphiphilic nanoparticles penetrate membranes by linking their activities to membrane capacitance, thickness, tension, intra-membrane potential, conductance, and lateral organization of peptides. By studying homogeneous and heterogeneous membranes that can be assembled to mimic a variety of cells, this work will generate new information about which lipid domains are preferred and test hypotheses that amphiphilic nanoparticles prefer defects, areas of higher curvature, and cholesterol-lean regions. Closely tied to the research, an educational and outreach program entitled INTERFACE will enable a wider range of people to engage in and interact with the research and technologies produced in the Principal Investigator's lab as a result of this project. INTERFACE includes public forums on the nature and context of bioactive nanoparticles, hands-on research activities for K-12 and undergraduate students, and support for STEM-focused journalism and improved science communication activities.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.