Four-component protein nanocages designed by programmed symmetry breaking

Sangmin Lee, Ryan D. Kibler, Green Ahn, Yang Hsia, Andrew J. Borst, Annika Philomin, Madison A. Kennedy, Buwei Huang, Barry Stoddard and David Baker ()
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Sangmin Lee: University of Washington
Ryan D. Kibler: University of Washington
Green Ahn: University of Washington
Yang Hsia: University of Washington
Andrew J. Borst: University of Washington
Annika Philomin: University of Washington
Madison A. Kennedy: University of Washington
Buwei Huang: University of Washington
Barry Stoddard: Fred Hutchinson Cancer Center
David Baker: University of Washington

Nature, 2025, vol. 638, issue 8050, 546-552

Abstract: Abstract Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures1,2. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry3–9, but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein–protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates10,11 and targeted delivery vehicles12,13.

Date: 2025
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DOI: 10.1038/s41586-024-07814-1

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