(261a) Interfacial Dynamics between Pathogenic Nanoparticles and Cell Membrane Surfaces

Small vesicles derived from live, biological cell membranes are ubiquitous in nature and found among both mammalian and bacterial cells. These vesicles range from the nano- to micro- scale in diameter and can serve a variety of purposes. Examples of such particles include exosomes, for membrane trafficking of proteins; microvesicles (MVs), derived from cancer cells; outer membrane vesicles (OMVs), produced by bacteria like E. Coli; and membrane-enveloped viruses, borne from infected mammalian cells. What is common to all these particles is that they are essentially cell membranes encapsulating an aqueous compartment filled with biological materials like proteins and RNA. Another common theme is that these particles are thought to be critical in cellular reprogramming. While this cellular reprogramming can serve physiological roles it also enables pathological changes. In the case of cancer, for example, vesicle-mediated cellular reprogramming leads to the formation of tumor-promoting microenvironments, biofilms in the case of bacteria, and the spread of infection in the case of viruses. Hence, gaining an understanding of how these particles interact with “host” cell surfaces and which specific material properties of host cell surfaces facilitate these interactions is important for the development of strategies to interrupt these outcomes. Improved understanding of how interfacial properties of cellular membranes modulate the dynamic interactions between particles and host cell surfaces, in turn, makes it possible to use that knowledge for beneficial purposes, like controlling the regrowth of damaged tissue, or designing next-generation particles for targeted drug delivery. But, our understanding of how microvesicles and cell surfaces interact is very limited. That is, how the particles interact with the cell surface and deliver their message is unknown in most cases, with one exception: viruses. Virus infection has been studied in much detail over decades. However, only recently has it become possible to study molecular-scale interactions of viruses with host cell membranes and the resulting consequences on virus entry and delivery of viral genomes across membranes. Detailed studies of these interactions are enabled by modern tools like microfluidics, biomimetic membrane materials, and sophisticated microscopy. Several groups, including the Daniel group, have pioneered single particle tracking (SPT) to directly observe virus binding to, and fusion with, host membranes for the successful delivery of viral RNA across cell membranes. Because individual virions can be monitored with SPT, details about on and off binding rates, binding residence times, and intermediate fusion steps like membrane merging and pore formation can be timed and analyzed for individuals and populations. This quantitative approach to characterizing the dynamic interactions of virus with host cell surface has provided critical new insights about virus infection, its dependence on the material properties of the membranes (e.g., composition, fluidity, charge, etc.), and pinpoints new targets for therapeutic intervention. Our recent work leverages the tools and biomimetic membrane materials we have pioneered for the study of dynamic interactions of viruses with host cell surfaces to understand the dynamic interactions of other kinds of microvesicular particles with their target cell surfaces. In this plenary talk, I will give an overview of our work on understanding pathogenic nanoparticle interactions with cell surfaces and the exciting, new directions possible for study, enabled by high resolution microscopy techniques and quantitative analysis.