Mechanistic insights on structure, topology and radiation effects on RNA nanomedicines

项目摘要 RNA疗法及其相应的纳米药物有望迅速改变 医疗保健。为了解决各种疾病的需求，基于RNA的技术必须在体内发挥作用 不同层次的生物相互作用，从全身(全身生物分布和免疫)到 组织和器官，到细胞内转运和内体释放。不幸的是，在肿瘤学方面，高效 脂质纳米粒(LNPs)向实体肿瘤的全身递送一直受到不良组织的困扰 积累在很大程度上是由于对这些材料之间的基本相互作用的知识的差距 和生物系统。在这里，我们建议研究结构-活性-关系(SAR) 通过使用化学和拓扑结构多样化的脂聚物库的纳米颗粒载体- 调整RNA-LNP的生物界面。利用条形码和串口深度机制相结合 分析，我们将测试我们的中心假设，即一系列定义的第一原则关系支配着 体内LNPs的生物物理相互作用。使用癌症模型，我们将把空间和时间关联起来 具有LNP生物物理化学性质的靶组织和细胞的mRNA积聚 生物界面。本项目的目标是建立一个物理化学性质的框架，以指导 基于RNA-LNP的肿瘤纳米药物研究进展。我们将通过追求目标来实现这一目标 目标1-LNPs生物界面的结构和拓扑微调。目标2--阐明 LNPs在全身、组织水平和细胞内分布方面的生物相互作用。目标 3-在多模式乳腺癌的背景下研究LNPs的生物相互作用和有效性 心理治疗。这项研究的直接成果将应用于推动使用 肿瘤学中的纳米技术。我们的项目将产生对LNP角色的批判性和详细的理解 生物界面及其对LNPs在复杂生物系统中命运的影响以及它们的有效性。这 无价的知识将极大地帮助整个纳米医学的未来发展。

PROJECT ABSTRACT RNA therapeutics and their corresponding nanomedicines are poised to rapidly change the landscape of healthcare. To address needs in various diseases, RNA-based technologies must function in vivo with biological interactions at various levels from whole body (systemic biodistribution and immunological) to tissues and organs, to intracellular trafficking and endosomal release. Unfortunately in oncology, efficient systemic delivery of lipid nanoparticles (LNPs) to solid tumors has been plagued by poor tissue accumulation largely due to a gap in the knowledge of fundamental interactions between these materials and biological systems. Here we propose to investigate the structure-activity-relationship (SAR) of nanoparticle carriers through use of a chemically and topologically diverse library of lipopolymers fine- tuning the biointerface of RNA-LNP. Utilizing a combined barcoding and serial in-depth mechanistic assays, we will test our central hypothesis that a defined series of first-principles relationships govern the biophysical interactions of LNPs in vivo. Using cancer models, we will correlate the spatial and temporal accumulation of mRNA at target tissues and cells with biophysicochemical properties of the LNP biointerface. The goal of this project is to establish a framework of physiochemical properties to guide the development of RNA-LNP based cancer nanomedicines. We will achieve this goal by the pursuing the following aims: Aim 1 - Structural and topological fine-tuning of LNPs biointerface. Aim 2 - Elucidate the biological interactions of LNPs with respect to whole-body, tissue-level, and intracellular distributions. Aim 3 - Investigate the biological interaction and efficacy of LNPs in the context of multimodal breast cancer therapy. The immediate outcomes of this research will be applied toward advancing the use of nanotechnology in oncology. Our project will yield a critical and detailed understanding of the role the LNP biointerface and its effects on the fate of LNPs in complex biological systems as well as their efficacy. This invaluable knowledge would greatly aid in future developments in nanomedicine as a whole.