Mechanoregulators of Nanoparticle-Cell Interactions at Tissue Interfaces

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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.