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Transforming cell-surface signatures into customizable protein functions

Nature Reviews Molecular Cell Biology volume 27, page 91 (2026)Cite this article

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Cells display a variety of molecules on their surfaces that are essential for processes such as communication, adhesion and immune recognition. Combinations of these molecules act as ‘signatures’ unique to each cell type or state. Most tools probe only one surface molecule at a time and can do little more than label or kill the targeted cell. This limits our ability to study tissue complexity, where heterogeneous and transient cell states have crucial roles, for instance during immune responses or in diseases. We therefore need new programmable tools that can detect multiple surface markers simultaneously and convert that information into defined protein outputs that label cells for imaging or proteomics analysis, signal to neighbouring cells or modulate specific pathways within the target cell.

By converting combinations of surface markers into highly selective protein functions, SMART offers new ways to study how cells interact within their tissue environments. For example, we engineered SMART to produce a ‘protein glue’ (called SpyCatcher003) selectively on cells displaying a specific pair of markers, for example, epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor 2 (HER2, also known as ERBB2), enabling the selective attachment of fluorescent and proteomics probes, enzymes or toxins to those cells. In another application, we used SMART to mimic paracrine signalling by generating and releasing the cytokine interleukin-1β from target cells to affect signalling in neighbouring cells. These examples demonstrate how SMART provides a versatile tool that enables precise, context-dependent protein activities to investigate and manipulate cellular behaviour or deliver therapeutics conditionally.

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  1. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Christian Kofoed

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  1. Christian Kofoed
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Correspondence to Christian Kofoed.

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The author has filed a provisional US patent application related to the original research discussed in this review.

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Kofoed, C. Transforming cell-surface signatures into customizable protein functions. Nat Rev Mol Cell Biol 27, 91 (2026). https://doi.org/10.1038/s41580-025-00925-1

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