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Induced proximity at the cell surface

Nature Biotechnology volume 43, pages 702–711 (2025)Cite this article

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Abstract

Molecular proximity is a governing principle of biology that is essential to normal and disease-related biochemical pathways. At the cell surface, protein–protein proximity regulates receptor activation, inhibition and protein recycling and degradation. Induced proximity is a molecular engineering principle in which bifunctional molecules are designed to bring two protein targets into close contact, inducing a desired biological outcome. Researchers use this engineering principle for therapeutic purposes and to interrogate fundamental biological mechanisms. This Review focuses on the use of induced proximity at the cell surface for diverse applications, such as targeted protein degradation, receptor inhibition and activating intracellular signaling cascades. We see a rich future for proximity-based modulation of cell surface protein activity both in basic and translational science.

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Fig. 1: Bifunctional inducers of proximity can elicit diverse biological effects at the cell surface through multiple mechanisms of action.
Fig. 2: Strategies for TPD via lysosome-trafficking receptors and cell surface E3 ligases.
Fig. 3: Strategies for receptor inhibition through induced phosphatase recruitment.
Fig. 4: Strategies for receptor activation through induced proximity.
Fig. 5: Induced proximity modalities acting between two cells.

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Acknowledgements

N.T. was supported by F32 Postdoctoral Fellowship F32GM143843. This work was supported by National Institutes of Health grant R01GM058867 (C.R.B.).

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Authors and Affiliations

  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Nicholas A. Till & Carolyn R. Bertozzi

  2. Sarafan ChEM-H, Stanford University, Stanford, CA, USA

    Nicholas A. Till, Muthukumar Ramanathan & Carolyn R. Bertozzi

  3. Department of Pathology, Stanford University, Stanford, CA, USA

    Muthukumar Ramanathan

  4. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Carolyn R. Bertozzi

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  1. Nicholas A. Till
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Correspondence to Carolyn R. Bertozzi.

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Competing interests

C.R.B. is a cofounder and scientific advisory board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Biosciences, Redwood Bioscience (a subsidiary of Catalent), OliLux Bio, InterVenn Bio, Grace Science, Firefly Bio, Neuravid and Valora Therapeutics. C.R.B. is also on the board of directors of Alnylam, OmniAb and Xaira Therapeutics. N.A.T. and M.R. declare no competing interests.

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Till, N.A., Ramanathan, M. & Bertozzi, C.R. Induced proximity at the cell surface. Nat Biotechnol 43, 702–711 (2025). https://doi.org/10.1038/s41587-025-02592-1

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