Nanoparticle-based therapies require imparting multiple functionalities onto nanoparticles of precise size and uniformity. However, such a requirement for particles with the relatively small diameters that are ideal for cellular internalization can be difficult to achieve using purely synthetic polymeric systems. We investigate the application of recombinant proteinbased nanoparticles, a strategy that takes advantage of the precision in genetic manipulation, as an alternative approach to fabricate particles for therapeutic applications. This enables molecular-level control of nanostructures to yield novel properties and biological interactions. Our research group has been investigating one such nanoparticle scaffold, the E2 subunit of pyruvate dehydrogenase, which has a diameter of 25 nm and exhibits unusually high thermostability. We have demonstrated that this nanoparticle can be re-engineered at the molecular level to accommodate drug molecules, exhibit pH-triggered assembly and drug release, target cancer cells, and modulate immune responses. These studies collectively reveal the tremendous potential of using natural protein scaffolds as a strategic departure point to create new biomaterials for therapeutic applications.