Four-component protein nanocages designed by programmed symmetry breaking

The paper of the Day describes a novel approach to design highly complex protein nanocages with tetrahedral, octahedral, and icosahedral symmetries. The key steps are:

1. Design of T=1 cages from homotrimeric building blocks.

2. Extraction of symmetric cyclic "crown" structures from the T=1 cages by replacing homotrimers with pseudosymmetric heterotrimers.

3. Assembly of the T=4 cages by docking the crown structures with additional homotrimers.The resulting T=4 cages have

4 distinct structural components and 6 distinct interfaces, a significant increase in complexity over previous designs.

The cages show good thermal and pH stability, and one icosahedral design was functionalized with an ASGPR-binding domain and shown to be internalized by liver cells. This approach can be extended to even higher symmetry assemblies.