Cells can ingest nanoparticles (NPs) that have distinct shapes. This project will create NPs using therapeutic proteins as building blocks. The proteins will be designed so that they can spontaneously form flexible, elongated particles. The proteins will incorporate clusters of molecules that will bind strongly and specifically to diseased cells. Controlling the size, shape, and chemistry of the NPs will determine where they accumulate in the human body after injection. If successful, this project could lead to new methods for targeted protein delivery in cancer and other diseases. Engagement of high school students in summer research opportunities, combined with extended research opportunities for undergraduate students will help develop a STEM workforce.
The project objective is to design a protein nanostructure platform capable of targeted intracellular delivery of proteins. A critical challenge is that the physical and chemical characteristics necessary for circulation are distinct from those necessary for cell uptake. Nanoscale dimensions and "stealth" chemistries are best for circulation whereas molecular-scale patterns of cell-binding ligands are best for cell uptake. The project will involve multiple steps. Modular protein engineering approaches will be applied to construct nanostructures with well-defined physical properties, using active enzymes as building blocks. Nanostructures with defined ligand clustering as well as ligand anisotropy will be created using unnatural amino acid (UAA) modification of protein oligomers. The physicochemical properties of these nanostructures that define important intracellular delivery outcomes will be characterized. Ultimately, the project will offer new fundamental insights into the design, construction, and growth of protein oligomers that assemble into specific nanoarchitectures. The expectation is that this will lead to new capabilities to design ?protein materials? that can address prohibitive barriers in systemic administration and delivery of intracellular proteins.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
