The design and fabrication of new drug delivery systems has been one emerging facet of bionanotechnology. Caged protein assemblies 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 pyruvate dehydrogenase core protein (E2) from Bacillus stearothermophilus forms a 25 nm nanocapsule structure with a hollow cavity suitable for drug encapsulation and delivery. The protein complex can be modified in three different regions: the (1) exterior surface, (2) interior cavity and (3) interface between subunits. In this investigation, we show that our engineered protein assembly exhibits unusual stability; we found the thermostability of the nanocapsule to be very high with an apparent melting temperature of 91.4 ± 1.4 °C. To evaluate the potential of this scaffold for cell targeting functionality, we show the expression and characterization of exogenous cancer targeting ligands on the outer surface. We can also design and incorporate internal mutations which alter the physicochemical properties of the internal cavity to encapsulate guest molecules. By manipulating the inter-subunit interface, we introduce a pH-dependent assembly that is correctly self-assembled at neutral pH, but disassembles in acidic conditions. Therefore, the unusually robust nature of this system and its amenability to modifications reveal its potential for drug delivery applications.

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