Mechanoregulators of Nanoparticle-Cell Interactions at Tissue Interfaces

摘要报表 一种不断演变的细胞外机械格局伴随着多种疾病的进展，包括 癌症、肺纤维化和高血压。而僵硬的组织对基因表达的影响，细胞 迁移，以及表型已经确立，这些变化如何影响纳米粒疗法的传递 了解较少，特别是对于承受动态力(如拉伸)的材料。常规体外培养 纳米粒子发现模型使用的塑料不具有反射组织的机械性能。这些 模型限制了传统筛查过程的有效性。因此，我的研究计划将 研究动态力如何影响纳米粒子的摄取和命运，并将此信息应用于设计更多 用于细胞进入的高效纳米颗粒。具体地说，我们将关注肺上皮组织和血管 内皮，两种具有重要输送途径的纳米治疗组织。为了支持这一目标，研究 主题1将研究底物机械如何调节细胞的纳米颗粒摄取途径。几乎所有人 纳米颗粒通过内吞作用进入体内。然而，不同的内吞途径的生产率可能会有所不同， 特别是在考虑了刚度和动态力的情况下。我们的目标是识别和了解 机械连接的调控过程将纳米颗粒引导到不同的吸收途径。为了实现这一目标， 我们将使用包含2D和3D拉伸的组织模型 生理/病理生理学组织环境。主题2侧重于了解细胞表面 当细胞受到不同的力时，结构会发生变化，特别是糖萼。确定中的关键更改 基于潜在的细胞靶向，糖基化结构将提供潜在的靶向特定细胞的途径 失调的物理环境。这些模型将与脂质体纳米颗粒设计相结合， 在复杂的细胞环境中促进向目标细胞的传递。总而言之，这项研究计划将 允许我们通过考虑细胞和多细胞的机械特性来重新想象细胞靶向 相互作用，以提高疗效、安全性和可控性，重新设计NP配方。

Summary Statement An evolving extracellular mechanical landscape accompanies the progression of multiple diseases including cancer, pulmonary fibrosis, and hypertension. While the influence of stiffening tissue on gene expression, cell migration, and phenotype is well established, how these changes affect delivery of nanoparticle therapeutics is less well understood, especially for materials that experience dynamic force (e.g., stretch). Conventional in vitro nanoparticle discovery models use plastics that do not have mechanical properties reflecting tissue. These models limit the effectiveness of conventional screening processes. Therefore, my research program will examine how dynamic forces impact nanoparticle uptake and fate and apply this information to design more efficient nanoparticles for cellular entry. Specifically, we will focus on lung epithelial tissue and vascular endothelium, two tissues with important delivery routes for nanotherapeutics. In support of this goal, research theme 1 will examine how substrate mechanics modulate the nanoparticle uptake pathway of cells. Nearly all nanoparticles enter through endocytosis. However, the productivity of different endocytosis routes can vary, especially when stiffness and dynamic forces are included. Our goal is to identify and understand how mechanically-linked regulatory processes direct nanoparticles to different uptake pathways. To achieve this goal, we will utilize tissue models that include 2D and 3D stretches that are observed in physiological/pathophysiological tissue environments. Theme 2 focuses on understanding how cell surface structures, particularly the glycocalyx, change when cells experience different forces. Identifying key changes in glycocalyx structures will present potential routes for targeting specific cells based on the underlying dysfunctional physical environment. These models will be combined with liposomal nanoparticle designs that facilitate delivery to target cells within complex cell environments. Taken together, this research program will allow us to reimagine cellular targeting by factoring in the mechanical characteristics of cells and multicellular interactions to redesign NP formulations with enhanced efficacy, safety, and control.