Biomimetic Design of Protein Nanomaterials for Hydrophobic Molecular Transport

Abstract Biomaterials such as self‐assembling biological complexes have a variety of applications in materials science and nanotechnology. The functionality of protein‐based materials, however, is often limited by the absence or locations of specific chemical conjugation sites. Here a new strategy is developed for loading organic molecules into the hollow cavity of a protein nanoparticle that relies only on non‐covalent interactions, and its applicability in drug delivery is demonstrated in breast cancer cells. Based on a biomimetic model that incorporates multiple phenylalanines to create a generalized binding site, the anti‐tumor compound doxorubicin is retained and delivered by redesigning a caged protein scaffold. Using structural modeling and protein engineering, variants of the E2 subunit of pyruvate dehydrogenase with varying levels of drug‐carrying capabilities are obtained. An increasing number of introduced phenylalanines within the scaffold cavity generally results in greater drug loading capacity. Drug loading levels greater than conventional nanoparticle delivery systems are achieved. The universal strategy can be used to design de novo hydrophobic binding domains within protein‐based scaffolds for molecular encapsulation and transport and increases the ability to attach guest molecules to this class of materials.