Adoptive Macrophage Transfers for Nanoparticle Delivery - ABSTRACT Immune cells will serve as next-generation vehicles to deliver cargo such as bioactive drugs and contrast agents to inflamed tissues. Due to their abundant expression of chemokine receptors, cells like macrophages have the capacity to infiltrate inflamed tissues with remarkable specificity. Researchers are exploiting this capability to direct the transport of attached nanoparticles containing drugs and other cargo to diseased tissues (e.g., from cancer, infectious diseases, autoimmune disorders, and cardiovascular disease). However, macrophages are living entities that can change their function in complex and sometimes unexpected ways when loaded with nanoparticles. Thus, there is a fundamental need to understand the interactions between macrophages and the nanoparticles they carry. To address this gap in knowledge, my laboratory will investigate two focus areas. First, we will study how the physical properties of nanoparticles affect macrophage phenotypes. Using nanofabrication, we will create nanoparticles that vary in size, shape, stiffness, and composition; direct their attachment onto, or internalization within, macrophages; and measure their responses using epigenomic, transcriptomic, and molecular phenotyping tools. This focus area will reveal differentially expressed genes that are involved in the macrophage responses to nanoparticle loadings of various design. In the second focus area, we will study the principal factors that govern cell-mediated transport of nanoparticles to inflamed tissues. Different macrophage- nanoparticle complexes will be made and injected into mice harboring different models of inflammation designed to recruit different subpopulations of immune cells. We will study the role of nanoparticle placement (i.e., onto the surfaces of cells versus within their interiors) as well as the role of macrophage phenotypes on their transport efficiency to inflamed tissues. The outcome of this work will be a set of design rules that predict macrophage- mediated transport of nanoparticles to inflamed tissues. Once established, these rules will be exploited to guide the design of new types of nanoparticles that interface with macrophages, promote specific phenotypes that are advantageous for specific treatments, and facilitate improved transport to those diseased sites. Such a capability will improve clinical efforts to use adoptively transferred macrophages to deliver drugs, vaccines, and contrast agents for a range of inflammatory diseases.
