Computational design of non-porous, pH-responsive antibody nanoparticles

Yang, E. C.; Divine, R.; Miranda, M. C.; Borst, A. J.; Sheffler, W.; Zhang, J. Z.; Decarreau, J.; Sarajovi, A.; Abedi, M.; Goldbach, N.; Ahlrichs, M.; Dobbins, C.; Hand, A.; Cheng, S.; Lamb, M.; Levine, P. M.; Chan, S.; Skotheim, R.; Fallas, J.; Ueda, G.; Lubner, J.; Somiya, M.; Khmelinskaia, A.; King, N. P.; Baker, D.

doi:10.1101/2023.04.17.537263

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bioRxiv · 10.1101/2023.04.17.537263

Computational design of non-porous, pH-responsive antibody nanoparticles

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Abstract

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and important for targeted delivery of biologics. We describe the design of octahedral non-porous nanoparticles with the three symmetry axes (four-fold, three-fold, and two-fold) occupied by three distinct protein homooligomers: a de novo designed tetramer, an antibody of interest, and a designed trimer programmed to disassemble below a tunable pH transition point. The nanoparticles assemble cooperatively from independently purified components, and a cryo-EM density map reveals that the structure is very close to the computational design model. The designed nanoparticles can package a variety of molecular payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between to 5.9-6.7. To our knowledge, these are the first designed nanoparticles with more than two structural components and with finely tunable environmental sensitivity, and they provide new routes to antibody-directed targeted delivery.

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Yang, E. C., Divine, R., Miranda, M. C., Borst, A. J., Sheffler, W., Zhang, J. Z., Decarreau, J., Sarajovi, A., Abedi, M., Goldbach, N., Ahlrichs, M., Dobbins, C., Hand, A., Cheng, S., Lamb, M., Levine, P. M., Chan, S., Skotheim, R., Fallas, J., Ueda, G., Lubner, J., Somiya, M., Khmelinskaia, A., King, N. P., Baker, D.. 2023-04-18. Computational design of non-porous, pH-responsive antibody nanoparticles. https://doi.org/10.1101/2023.04.17.537263

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