(15g) Peptide Engineering for Targeted, Intracellular Delivery of siRNA and Proteins (INVITED SPEAKER)

Protein nanostructures with tunable chemistries would be extremely useful in a wide variety of applications ranging from biocatalysis to biopharma. Biopharmaceutical products are especially well-posed for impact: drugs such as monoclonal antibodies, peptides, and enzymes are rapidly transforming the global pharmaceutical industry, and biologics represented 35% of all new FDA approvals between 2010 and 2016. Moreover, the pipeline has a dearth of intracellular protein drug candidates, even though intracellular proteins comprise 61% of the proteome and have mulitple predicted therapeutic applications. In fact, essentially all protein drugs to date have been restricted to vascular targets or targets on the cell surface, referred to as the ‘accessible target space.'

We are designing peptide functionalization approaches in protein nanostructures that will enable improved control over intracellular targeting and delivery of siRNA and protein cargoes via improved control over the display of peptide ligands. Our specific goals are to demonstrate the use of versatile and modular protein engineering approaches (e.g., ‘Tag/Catcher’ chemistries; unnatural amino acid [UAA]/‘click’ chemistries) to create protein nanostructures that can be targeted and delivered with high efficiency, cell specificity, and no activity loss. Herein, we will describe approaches to enhance targeted protein delivery into inflammatory breast cancer (IBC) cells by tuning the number and density of epidermal growth factor receptor (EGFR) ligands, and by altering the size of the nanostructures used for delivery.