High-density Lipoprotein Mimetic Nanoparticles: Roles in Therapy and Probing Intercellular CommunicationPublic
Bio-inspired materials have a distinct advantage over other materials by virtue of their mimicry of nature’s own products, which have been subjected to the inimitable tests of time and evolutionary pressure. Here we have taken instruction from natural nanostructures that are ubiquitous across the animal kingdom, namely high-density lipoproteins (HDL). These native nanoparticles circulate in the bloodstream and transport lipids between organs and tissues. Primary among the lipids that HDLs and other lipoproteins transport is cholesterol. Cholesterol is an indispensable component of animal cell membranes that regulates a host of biological processes such as ligand-receptor interactions, endocytosis, membrane protein scaffolding, intercellular communication, second messenger signaling and others. There is a vast possibility space for applications of HDL-mimicking nanoparticles (HDL NP), only a fraction of which have been explored to date. In this thesis, we explore three primary applications: 1) anti-atherosclerosis therapy by way of cholesterol transport, 2) probing the cholesterol-dependence of intercellular signaling, particularly via exosomes, and 3) inhibiting viral infection by targeted depletion of cholesterol. In addition to the application of these materials for translational purposes, we also report fundamental strides in HDL NP synthesis. In particular, we describe the fabrication of nanoparticles that mimic mature, spherical HDLs using novel, small molecule-phospholipid conjugates as core scaffolds. These materials are distinctive for several reasons: 1) they represent a successful synthesis of monodisperse lipid nanoparticles in the sub-20 nm size regime, which is extremely challenging without using an inorganic template, 2) most synthetic HDL mimics resemble immature, discoidal HDL, while these particles represent a genuine functional mimic of mature spherical HDL (the most abundant HDL sub-species in humans), 3) these particles possess a dynamic, hydrophobic core that can accommodate a diverse range of hydrophobic cargo, and 4) these particles reduce atherosclerotic burden in LDL-R-/- mice by approximately 70%. The second major focus of this dissertation is on the cholesterol dependence of exosome communication in the setting of cancer. Others have shown that primary tumors can establish long-range communication with distant organ sites to transform them into fertile soil for circulating tumor cells to implant and proliferate, a process called pre-metastatic niche formation. Tumor-derived exosomes can be potent mediators of pre-metastatic niche formation. Here we explore the role of prostate cancer exosomes as promoters of pre-metastatic niche formation in bone, and we interrogate the cholesterol dependence of this intercellular communication. We show that exosome-mediated communication between prostate cancer cells and bone marrow myeloid cells is highly sensitive to the cholesterol burden of the target myeloid cell population. In particular, reducing cellular cholesterol in myeloid cells in a targeted fashion using HDL NPs reduces the transduction of prostate cancer exosome signaling, ultimately inhibiting both pre-metastatic niche formation and metastasis. HDL NPs enabled us to interrogate the cholesterol dependence of exosome communication in vivo with greater precision than other methods due to the intrinsic targeting properties of HDL NPs and their favorable toxicity profile. HDL NPs enabled us not only to identify that cholesterol is a critical parameter for this intercellular communication, but also to demonstrate that cholesterol modulation may be a viable approach to metastasis therapy and prevention. Finally, we demonstrate that HDL NPs can function as anti-viral agents to inhibit infection of a SARS-CoV-2 pseudovirus by targeted depletion of cellular cholesterol.
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