A chimeric viral platform for directed evolution in mammalian cells

Alexander J. Cole, Christopher E. Denes, Cesar L. Moreno, Lise Hunault, Thomas Dobson, Daniel Hesselson () and G. Gregory Neely ()
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Alexander J. Cole: The University of Sydney
Christopher E. Denes: The University of Sydney
Cesar L. Moreno: The University of Sydney
Lise Hunault: The University of Sydney
Thomas Dobson: The University of Sydney
Daniel Hesselson: The University of Sydney
G. Gregory Neely: The University of Sydney

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Directed evolution is a process of mutation and artificial selection to breed biomolecules with new or improved activity. Directed evolution platforms are primarily prokaryotic or yeast-based, and stable mammalian systems have been challenging to establish and apply. To this end, we develop PROTein Evolution Using Selection (PROTEUS), a platform that uses chimeric virus-like vesicles to enable extended mammalian directed evolution campaigns without loss of system integrity. This platform is stable and can generate sufficient diversity for directed evolution in mammalian systems. Using PROTEUS, we alter the doxycycline responsiveness of tetracycline-controlled transactivators, generating a more sensitive TetON-4G tool for gene regulation with mammalian-specific adaptations. PROTEUS is also compatible with intracellular nanobody evolution, and we use it to evolve a DNA damage-responsive anti-p53 nanobody. Overall, PROTEUS is an efficient and stable platform to direct evolution of biomolecules within mammalian cells.

Date: 2025
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DOI: 10.1038/s41467-025-59438-2

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