Two-tier supramolecular encapsulation of small molecules in a protein cage

Expanding protein design to include other molecular building blocks has the potential to increase structural complexity and practical utility. Nature often employs hybrid systems, such as clathrin-coated vesicles, lipid droplets, and lipoproteins, which combine biopolymers and lipids to transport a broader range of cargo molecules. To recapitulate the structure and function of such composite compartments, we devised a supramolecular strategy that enables porous protein cages to encapsulate poorly water-soluble small molecule cargo through templated formation of a hydrophobic surfactant-based core. These lipoprotein-like complexes protect their cargo from sequestration by serum proteins and enhance the cellular uptake of fluorescent probes and cytotoxic drugs. This design concept could be applied to other protein cages, surfactant mixtures, and cargo molecules to generate unique hybrid architectures and functional capabilities. Protein cages are used for encapsulation of macromolecules such as proteins and nucleic acids. Here, the authors report a strategy to encapsulate poorly soluble small molecules within porous protein cages through capsid-templated micelle formation and show that the resulting lipoprotein-like cages enhance the cellular delivery of these molecules.