Synthetic Lipid Switches for Controlling Liposome Assembly and Release

脂质体是一种很有前途的分子载体，可以增强治疗剂的递送，因为它们能够包封大量的货物，并以限制副作用的方式将这些内容物递送到细胞中。虽然在利用脂质体改善输送特性方面取得了很大进展，但仍存在一些挑战。特别是，控制封装内容物释放的位置和时间的能力一直是一个长期存在的障碍。在这个项目中，一种新的控制脂质体释放的范例正在被追求，其中货物的排放是由病变细胞内和周围过度表达的特定生物分子引起的。为此，将开发由合成脂质组成的设计脂质体，使其在生物物种存在的情况下发生组装特性的变化，从而导致内容物的释放。该项目将通过提高操纵脂质体组装特性的能力，以及对这些特性在不同化学和生物条件下发生的变化进行编程，从而导致基础科学进步。这项工作还将促进国民健康，因为它将最终产生旨在改善脂质体治疗特性的新技术。脂质体是生物相容性的纳米载体，既可以包封疏水分子，也可以包封亲水分子。因此，人们对开发设计脂质体的兴趣很大，通过这种设计脂质体可以控制它们的自组装特性。特别感兴趣的是在不同刺激存在时触发封装内容物释放的能力。在这个项目中，提出了新的策略来触发与化学物质的结合相互作用驱动的脂质体释放。为此，可切换的脂质将被开发出来，它们被设计成经历构象变化，从而破坏膜特性的稳定性，并在与目标分子形成结合相互作用时触发内容物释放。本研究将探讨如何设计合成脂质类似物来调节脂质体的超分子性质。特别是，可切换的脂质类似物将被开发，其中包含嵌入其结构中的分子识别基团，用于结合目标分子。这些脂质被设计成它们最初会形成稳定的膜双层。然而，在与靶分子形成宿主-客体结合相互作用后，这些脂质被设想发生构象变化，使脂质体膜不稳定，从而改变脂质包装和自组装特性，并触发内容物的释放。在本项目中进行的研究将需要对这些可切换脂质的设计、合成和评估进行全面的努力，以评估和优化控释特性。最初的研究将集中于了解含有这些脂质的脂质体的基本释放特性。随后，这些设计脂质体渗透细胞并递送具有不同性质的胶囊货物的能力将被评估。通过这种方式，所提出的研究为调节脂基纳米材料的自组装特性提供了创新的方法。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。

Non-Technical SummaryLiposomes represent promising molecular carriers for enhancing the delivery of therapeutic agents due to their ability to encapsulate a wide range of cargo and deliver these contents to cells in a manner that limits side effects. While great advancements have been made to improve delivery properties using liposomes, several challenges remain. In particular, the ability to control the location and time of the release of encapsulated contents has been a longstanding obstacle. In this project, a novel paradigm for controlled release from liposomes is being pursued by which the discharge of cargo is caused by specific biological molecules that are overexpressed in and around diseased cells. Toward this end, designer liposomes composed of synthetic lipids will be developed that undergo changes in assembly properties in the presence of biological species to cause the release of contents. This project will result in fundamental scientific progress by advancing the ability to manipulate the assembly properties of liposomes and to program changes in these properties that occur in response to different chemical and biological conditions. This work will also advance national health as it will culminate in new technology aimed at improving the therapeutic properties of liposomes.Technical SummaryLiposomes exhibit many favorable attributes as they are biocompatible nanocarriers that can encapsulate both hydrophobic and hydrophilic molecular cargo. As such, there has been significant interest in developing designer liposomes by which their self-assembly properties can be controlled. Of particular interest is the ability to trigger the release of encapsulated contents when in the presence of different stimuli. In this project, novel strategies are proposed for triggering release from liposomes driven by binding interactions with chemical species. Toward this end, switchable lipids will be developed that are designed to undergo conformational changes that destabilize membrane properties and trigger content release upon the formation of binding interactions with target molecules. This research will investigate how the design of synthetic lipid analogs can be used to modulate the supramolecular properties of liposomes. In particular, switchable lipid analogs will be developed that contain molecular recognition groups embedded within their structures for the binding of target molecules. These lipids are designed such that they will initially form stable membrane bilayers. However, upon the formation of host-guest binding interactions with target molecules, these lipids are envisaged to undergo conformational changes that destabilize the liposome membrane, thereby altering lipid packing and self-assembly properties, and triggering the release of contents. The research performed during this project will entail comprehensive efforts for the design, synthesis and assessment of these switchable lipids to evaluate and optimize controlled release properties. Initial studies will be focused on understanding the fundamental release properties of liposomes containing these lipids. Subsequently, the ability of these designer liposomes to infiltrate cells and deliver encapsulated cargo with different properties will be evaluated. In this way, the proposed studies provide innovative approaches for modulating the self-assembly properties of lipid-based nanomaterials.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.