Caged protein systems have been proposed as general drug carriers since they form highly symmetric nanoscale architectures that offer the potential to be tailored according to the desired application. The E2 subunit of the pyruvate dehydrogenase protein from Bacillus stearothermophilus forms a 25-nm nanocapsule structure with a hollow cavity. We produced a variant of this protein consisting only of the structural core, and found the thermostability of this self-assembled scaffold to be unusually high, with an onset unfolding temperature of 81.1°C and an apparent midpoint unfolding temperature of 91.4°C. To evaluate the potential of this scaffold for encapsulation of guest molecules in the internal cavity, we made variants at residues 381 and 239 which altered the physicochemical properties of the hollow internal cavity. These mutants, yielding 60 and 120 mutations within this cavity, assembled into the correct architecture and exhibited high thermostability that was also comparable to the wild-type scaffold. To show the applicability of this scaffold for small molecule encapsulation, fluorescein-5-maleimide and Alexa Fluor 532 C5-maleimide were coupled to the internal cavity. We demonstrate that these mutations can introduce non-native functionality and enable molecular encapsulation within the cavity while still retaining the dodecahedral structure. The unusually robust nature of this scaffold and its amenability to internal changes reveal its potential for nanoscale applications.