Mechanoregulators of Nanoparticle-Cell Interactions at Tissue Interfaces

简要说明 不断发展的细胞外机械景观伴随着多种疾病的进展，包括 癌症、肺纤维化和高血压。而硬化组织对基因表达、细胞 迁移和表型已经很好地建立，这些变化如何影响纳米颗粒治疗剂的递送， 不太好理解，特别是对于经历动态力的材料（例如，拉伸）。常规体外 纳米颗粒发现模型使用不具有反射组织的机械性能的塑料。这些 模型限制了常规筛选过程的有效性。因此，我的研究计划将 研究动态力如何影响纳米颗粒的吸收和命运，并将此信息应用于设计更多 有效的纳米颗粒进入细胞。具体而言，我们将重点关注肺上皮组织和血管 内皮细胞是两种具有纳米治疗重要递送途径的组织。为了实现这一目标，研究 主题1将研究基质力学如何调节细胞的纳米颗粒摄取途径。几乎所有 纳米颗粒通过内吞作用进入。然而，不同内吞途径的生产率可以变化， 特别是当包括刚度和动态力时。我们的目标是识别和理解 机械连接的调节过程将纳米颗粒引导至不同的摄取途径。为了实现这一目标， 我们将利用组织模型，包括2D和3D拉伸，观察到在 生理/病理生理组织环境。主题2关注于理解细胞表面 当细胞受到不同的力时，结构，特别是糖萼会发生变化。确定关键变化， 糖萼结构将根据潜在的细胞毒性， 功能失调的物理环境。这些模型将与脂质体纳米颗粒设计相结合， 有助于在复杂的细胞环境中递送至靶细胞。总的来说，这项研究计划将 使我们能够通过考虑细胞和多细胞的机械特征来重新构想细胞靶向 通过这种相互作用，重新设计NP制剂，提高疗效，安全性和控制。

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.