Synthetic Lipid Switches for Controlling Liposome Assembly and Release

非技术概述脂质体代表了用于增强治疗剂递送的有前景的分子载体，因为它们能够包封广泛的货物并以限制副作用的方式将这些内容物递送至细胞。虽然已经取得了很大的进步，以改善使用脂质体的递送性质，仍然存在一些挑战。特别是，控制胶囊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。在该项目中，正在追求一种用于从脂质体控制释放的新范例，通过该范例，由在患病细胞中和周围过表达的特定生物分子引起货物的排出。为此，将开发由合成脂质组成的设计脂质体，其在生物物种的存在下经历组装性质的变化以引起内容物的释放。该项目将通过提高操纵脂质体组装特性的能力，以及对响应不同化学和生物条件而发生的这些特性的变化进行编程，从而实现基础科学进步。这项工作也将促进国民健康，因为它将在旨在改善脂质体的治疗性能的新技术中达到高潮。技术概述脂质体具有许多有利的属性，因为它们是生物相容性纳米载体，可以包封疏水和亲水分子货物。因此，人们对开发可以控制其自组装性质的设计脂质体产生了极大的兴趣。特别令人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，触发释放的脂质体驱动的结合相互作用与化学物种。为此，将开发可转换脂质，其被设计为经历构象变化，使膜特性不稳定并在与靶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的脂质类似物可以用来调节脂质体的超分子性质。特别是，将开发可转换的脂质类似物，其结构中包含嵌入的分子识别基团，用于结合靶分子。这些脂质被设计成使得它们最初将形成稳定的膜双层。然而，在与靶分子形成主客体结合相互作用后，设想这些脂质经历使脂质体膜不稳定的构象变化，从而改变脂质包装和自组装性质，并触发内容物的释放。在该项目期间进行的研究将需要对这些可转换脂质的设计，合成和评估进行全面的努力，以评估和优化控释特性。最初的研究将集中在了解含有这些脂质的脂质体的基本释放特性。随后，将评估这些设计脂质体渗透细胞并递送具有不同性质的包封货物的能力。通过这种方式，拟议的研究提供了调节脂质基纳米材料自组装特性的创新方法。该奖项反映了NSF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.