Nano-Bio Interactions at the Surface of Pulmonary Surfactant Films

随着纳米技术的快速发展和纳米消费产品的广泛普及，纳米颗粒（NPs）对环境、健康和安全（EHS）的潜在不利影响日益受到关注，其特征尺寸小于100纳米。大多数NPs重量轻，可呼吸。NPs一旦被吸入，就会渗入肺部，干扰呼吸功能。整个肺表面覆盖着一层脂质蛋白肺表面活性剂（PS）膜，它具有宿主防御和表面张力降低的重要生理功能。因此，吸入的NPs和PS膜之间的相互作用代表了肺部最初的纳米生物现象。这种相互作用决定了吸入NPs的命运及其潜在的治疗或毒理学作用。该提案将使用PI实验室开发的新型实验和计算技术来研究NP-PS相互作用的详细机制。这些技术允许高保真地模拟空气污染情景，其中NPs被吸入并沉积在PS膜的表面。使用这些模型系统，将彻底评估NPs和纳米产品（如含有np的喷雾剂和油漆）的潜在环境危害。该项目将特别侧重于研究婴儿和儿童的可吸入性NP的潜在风险，他们脆弱的呼吸系统使他们比成年人更容易接触NP。这项拟议的研究将有助于提供一个有用的标准来规范和监督纳米技术的商业应用，以实现更安全和可持续的发展。本课题的研究目的是研究空气工程纳米颗粒（NPs）与天然肺表面活性剂（PS）相互作用的详细生物物理化学机制。本研究的新颖性主要体现在以下两个方面。首先，NP-PS相互作用将使用多尺度体外和硅模拟相结合的方法进行研究。体外研究依赖于生物物理模拟，使用PI实验室最近开发的一种新颖的实验方法。有了这个体外模型，PS膜上的纳米生物相互作用将通过完全控制的NP气溶胶剂量法和生理相关的呼吸条件来模拟。硅研究依赖于高保真分子动力学模拟，可以探测NP在PS膜上易位的详细分子机制。二是首次全面研究与肺液接触的NPs结合的生物分子冠状病毒，即所谓的PS生物分子冠状病毒。通过相关的高精度质谱分析和分子动力学模拟，该项目将以前所未有的细节揭示PS生物分子日冕的生化组成和生物物理构象。这项研究有望显著推进目前对呼吸系统中纳米生物相互作用的理解，并为纳米技术对EHS的影响提供新的见解。这一提议的广泛影响是丰富而多样的。在体外和硅片模拟中开发的这一建议是探索纳米技术的EHS影响的经济有效的手段。拟议的研究将补充目前从细胞培养和动物模型中获得的纳米毒理学知识。该研究揭示的生物物理化学机制对于设计基于np的肺给药以及更好地理解与空气污染和颗粒损伤相关的呼吸系统疾病的病理生理具有明确的变革价值。在与当地医疗保健提供者合作的情况下，预防传染计划开展了一些活动，以提高公众对婴儿和儿童可呼吸性新型冠状病毒潜在风险的认识。鉴于夏威夷大学的独特地理位置，PI致力于促进夏威夷原住民、太平洋岛民以及其他未被充分代表的群体和低收入家庭的学生的参与。PI还将开发具有跨学科组成部分的本科和研究生工程课程，并帮助加强研究和教育的基础设施。

PI: Zuo, Yi#1604119The rapid development of nanotechnology and a widespread proliferation of nano-enabled consumer products post an increasing concern of the potential adverse environment, health, and safety (EHS) impacts of nanoparticles (NPs), which feature a characteristic size less than 100 nm. Most NPs are lightweight and respirable. Once inhaled, NPs can penetrate into the lungs and interfere with the respiratory function. The entire surface of the lungs is lined with a lipid-protein pulmonary surfactant (PS) film which serves an important physiological function of host defense and surface tension reduction. Interactions between inhaled NPs and the PS film hence represent the initial nano-bio phenomena in the lungs. Such interactions determine the fate of the inhaled NPs and their potential therapeutic or toxicological effects. This proposal will investigate the detailed mechanism of NP-PS interactions using novel experimental and computational techniques developed in the PI's laboratory. These techniques allow high-fidelity simulations of air pollution scenarios in which NPs are inhaled and deposited at the surface of the PS film. Using these model systems, potential environmental hazards of NPs and nano-enabled products, such as NP-containing sprays and paints, will be thoroughly evaluated. The PI will specifically focus on studying the potential risk of respirable NPs for infants and children whose fragile respiratory system makes them more vulnerable to NP exposure than adults. The proposed study will help provide a useful metric for regulating and overseeing commercial applications of nanotechnology towards a safer and sustainable development. The research goal of this proposal is to study the detailed biophysicochemical mechanisms by which airborne engineered nanoparticles (NPs) interact with natural pulmonary surfactant (PS). This research is highly novel due to the following two main perspectives. First, NP-PS interactions will be studied using a combined approach of multiscale in vitro and in silico simulations. The in vitro study relies on biophysical simulations using a novel experimental methodology recently developed in the PI's laboratory. With this in vitro model, nano-bio interactions at the PS film will be mimicked with fully controlled NP aerosol dosimetry and under physiologically relevant respiratory conditions. The in silico study relies on high-fidelity molecular dynamics simulations which allow probing the detailed molecular mechanism of NP translocation across the PS film. Second, the PI will carry out the first comprehensive study of the biomolecular corona bound to NPs in contact with lung fluids, i.e., the so-called PS biomolecular corona. With correlated high-precision mass spectrometry and molecular dynamics simulations, the proposed project will reveal the biochemical composition and biophysical conformation of the PS biomolecular corona with unprecedented details. This research is expected to significantly advance current understanding of nano-bio interactions in the respiratory system and to provide novel insight into the EHS impacts of nanotechnology.The broader impacts of this proposal are rich and multifarious. In vitro and in silico simulations developed in this proposal are cost-effective means of exploring the EHS impacts of nanotechnology. The proposed study will complement the current nanotoxicological knowledge obtained from cell culture and animal-models. The biophysicochemical mechanism revealed by this study has clear transformative values for designing NP-based pulmonary drug delivery and for better understanding the pathophysiology of respiratory diseases related to air pollution and particle insult. In collaboration with local healthcare providers, the PI is engaged in activities of increasing the public awareness of the potential risk of respirable NPs for infants and children. Given the unique location of the University of Hawaii, the PI is dedicated to promoting participation of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups and low-income families. The PI will also develop undergraduate and graduate engineering curricula with interdisciplinary components, and help enhance the infrastructure for research and education.