ERI: The impact of ionizable lipid chemistry and targeting ligands on biological interactions of lipid nanoparticles

脂质纳米颗粒是一种超小型药物输送平台，可以包装治疗药物，使其比自由治疗药物更安全、更有效。在这个项目中，研究小组旨在了解脂质纳米颗粒的设计如何影响它们向细胞和组织输送高水平药物的能力。尽管研究人员知道脂质纳米颗粒的设计会影响其有效性，但其发生的确切机制仍然难以捉摸。在这里，研究小组将采取基本的和机械的方法来了解脂质的化学结构如何影响纳米粒子与细胞和组织的相互作用。该奖项将允许一名研究生和两名本科生参与这项研究，为罗文大学生物医学工程专业的学生提供特殊的研究机会。此外，该项目将通过独特的合作伙伴关系，从当地社区大学南泽西郡罗文学院招收一名学生。最终，这项工作的成功完成将使药物递送研究人员能够专门设计脂质，以改善广泛生物应用的药物递送。本项目的目的是研究电离脂质化学和脂质纳米颗粒的生物相互作用之间的结构-功能关系。由于脂质纳米颗粒在辉瑞和Moderna COVID-19疫苗中的应用，它们已成为转译药物递送的前沿。脂质纳米颗粒由可电离的脂质、胆固醇、磷脂和聚乙二醇与治疗性核酸络合而成。尽管近年来脂质纳米颗粒在临床方面取得了进展，但人们对其组成和理化性质如何影响其与生物系统的相互作用知之甚少。已经确定的是，可电离脂质化学决定了它们如何与细胞和组织相互作用以驱动药物递送效率。然而，关于电离脂质结构影响脂质纳米颗粒如何与细胞和组织相互作用的精确方法，在知识方面存在重大差距。在这里，研究小组将采取基础和机制的方法来评估脂质纳米颗粒组成如何影响分子、细胞和组织水平上的生物相互作用。总体假设是，饱和程度、烷基尾长度和可电离脂质的尾分支驱动脂质纳米颗粒的行为，包括稳定性、细胞摄取、细胞质输送、组织特异性和穿透性。研究目标是：(1)合成一系列新的可电离脂质，并评估可电离脂质结构如何影响脂质纳米颗粒的稳定性和蛋白质冠的形成；(2)评估可电离脂质化学（支链/线性、饱和度、尾长度）如何影响递送、摄取、内体逃逸和组织渗透。除了这些研究目标，这个项目还有几个教育目标。该奖项将允许一名研究生和两名本科生参与这项研究，为罗文大学生物医学工程专业的学生提供特殊的研究机会。此外，该项目将通过独特的合作伙伴关系，从当地社区大学南泽西罗文学院招收一名学生。本文所描述的工作有可能通过增强我们对可电离脂质化学如何影响生物系统中相互作用的理解来改变脂质纳米颗粒的开发和临床前测试方式。最终，这将使药物递送社区能够通过高效和数据驱动的方法设计下一代平台。该奖项反映了美国国家科学基金会的法定使命，并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，被认为值得支持。

Lipid nanoparticles are ultrasmall drug delivery platforms that can package therapeutics, making them safer and more efficacious than the free therapeutics. In this project, the research team aims to understand how the design of lipid nanoparticles impacts their ability to enable high levels of drug delivery to cells and tissues. Although researchers know that the design of lipid nanoparticles impacts their effectiveness, the precise mechanisms by which this occurs remains elusive. Here, the research team will take a fundamental and mechanistic approach to understand how the chemical structure of the lipids impacts how the nanoparticles interact with cells and tissues. This award will enable the inclusion of one graduate student and two undergraduate students on this research, providing exceptional research opportunities to Biomedical Engineering students at Rowan University. Further, the project will enable the recruitment of one student from Rowan College of South Jersey, the local community college, through a unique partnership. Ultimately, the successful completion of this work will allow drug delivery researchers to specifically design lipids for improved drug delivery for a wide range of biological applications. The goal of this project is to study structure-function relationships between ionizable lipid chemistry and the biological interactions of lipid nanoparticles. Lipid nanoparticles have emerged at the forefront of translational drug delivery due to their use in the Pfizer and Moderna COVID-19 vaccines. Lipid nanoparticles are comprised of ionizable lipids, cholesterol, phospholipids, and poly(ethylene) glycol complexed with therapeutic nucleic acids. Despite the recent clinical advancements of lipid nanoparticles, remarkably little is known about how their composition and physicochemical properties impact their interactions with biological systems. It has been established that ionizable lipid chemistry dictates how they interact with cells and tissues to drive drug delivery efficiency. However, there is a major gap in knowledge regarding the precise means by which ionizable lipid structure influences how lipid nanoparticles interact with cells and tissues. Here, the research team will take a fundamental and mechanistic approach to evaluate how lipid nanoparticle composition impacts biological interactions at the molecular, cellular, and tissue levels. The overarching hypothesis is that the degree of saturation, alkyl tail length, and tail branching of the ionizable lipids drives how lipid nanoparticles behave including stability, cell uptake, cytosolic delivery, and tissue specificity and penetration. The research objectives are to: (1) synthesize an array of new ionizable lipids and assess how ionizable lipid structure impacts lipid nanoparticle stability and protein corona formation, and (2) evaluate how ionizable lipid chemistry (branched/linear, degree of saturation, tail length) impacts delivery, uptake, endosomal escape, and tissue penetration. In addition to these research objectives, this project has several educational goals. This award will enable the inclusion of one graduate student and two undergraduate students on this research, providing exceptional research opportunities to Biomedical Engineering students at Rowan University. Further, this project will enable the recruitment of one student from Rowan College of South Jersey, the local community college, through a unique partnership. The work described herein has the potential to transform the way lipid nanoparticles are developed and tested preclinically by enhancing our understanding of how ionizable lipid chemistry impacts interactions in biological systems. Ultimately, this will enable the drug delivery community to engineer next-generation platforms created through an efficient and data-driven approach.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.