Engineering glycoprotein nanocages for cellular targeting and cargo delivery

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The ability to design nanostructures has revolutionized biomedicine, bioprocesses and electronics. Although advancements in nanotechnology and protein design have been substantially widespread, certain classes of biomolecules remain understudied. Glycoproteins, in particular, require stringent production systems and some are particularly unstable – making nanotechnology development of glycoproteins challenging. It is predicted that over half of human proteins have modifications that lead to their glycosylation. Furthermore, their multimerization regulates a variety of biological processes including gene expression, activity of receptors, and cell-cell adhesion. Thus, fundamental structure/function advances related to the multimerization of glycosylated biomolecules will directly impact nanotechnology advancements. My research in protein design and glycobiology has previously shown that self-assembling protein cages can be used for the external display of a viral glycoprotein, by optimizing its recognition by antibodies. By leveraging my expertise and resources, I want to further investigate the fundamentals of protein nanoparticle assembly and use protein engineering and biophysical techniques to broaden the development of stable glycoprotein nanocages. The objective of my research program is to uncover the fundamentals of protein nanoparticle self-assembly in mammalian cells in order to engineer the transport of multimerized glycoproteins on vehicles with loaded cargo. Aim 1 is to study the self-assembly of protein cages genetically fused to two types of glycoproteins for their external display: 1) oligomeric glycoproteins, and 2) antibody glycoproteins. In Aim 2, my team will study the fundamentals of protein encapsulation in the hollow center of the glycoprotein nanocages, with the objective to discover conditions under which all components are structurally-sound and deliverable to cells. HQPs will perform extensive biophysical, structural and functional characterization of glycoprotein nanocages to ultimately provide insights into glycoprotein design and uncover the fundamentals that govern glycoprotein nanocage interactions with cell-surface receptors. The topics, strategies, infrastructure and techniques used in my research program will provide HQPs with a tailored training in nanotechnology and high-throughput protein chemistry within a world-class research environment. Glycoproteins are widely dispersed in all biological processes – therefore discoveries made in glycoprotein nanocage manipulation have the potential to be broadly applicable and impactful in all areas where these nanotechnologies are used, such as imaging, cellular biology and biomedical engineering.