Modular engineering and in vivo library selection of tissue-targeting protein nanoparticles

Abstract

Targeted delivery remains one of the greatest challenges and opportunities in drug development. In Chapter 1, I review these challenges and opportunities through the lens of the principles of applying self-assembling protein nanomaterials to therapeutic delivery. In Chapter 2, I report an in vivo library selection platform based on protein nanoparticles that encapsulate their own genome. Our selection platform offers a unique tool to optimize protein-based therapeutic performance in a living mammal, a complex physiological environment that cannot yet be comprehensively modeled in silico or in vitro, and to identify targeting ligands of interest. In Chapter 3, I report results towards modularly reprogramming synthetic nucleocapsids for targeted chemotherapeutic delivery by altering both the displayed targeting domains and the encapsulated cargo. I discuss potential future directions in Chapter 4. Together, these results provide new insights and methods for developing self-assembling nanomaterials for in vivo targeted delivery.