Spatially resolved cell tagging and surfaceome labeling via targeted photocatalytic decaging

Spatially resolved in situ tagging of the cell of interest is crucial for in-depth mechanistic dissection of multicellular architectures or processes. With continuing interest in bioorthogonal photocatalytic decaging chemistry, we herein report the extracellular-targeted photocatalytic decaging system (CAT-Ex) for spatially resolved cell tagging and surface proteome profiling under living conditions. An antibody-conjugated photocatalysis system was established and extensively validated, enabling photocatalytic decaging of biotin precursors and proximal quinone methide probes on target cells. Visible-light-controlled selective cell tagging in cell mixture as well as in primary cells from tumor xenografts were demonstrated. Spatially resolved membrane proteome profiling was further achieved by coupling quinone methide decaging chemistry with CAT-Ex, revealing a potential microdomain protein cluster surrounding the endogenous HER2 receptor. Finally, we expanded our strategy to photocatalytic prodrug decaging for selective tumor cell killing, establishing CAT-Ex as a general platform for diverse photo-controlled molecular manipulations on targeted cells with spatial-temporal precision.

Automated summary

In this study, we report a extracellular-targeted photocatalytic decaging system for spatially resolved cell tagging and surface proteome profiling. By conjugating an antibody to the photocatalysis system, we achieved targeted photocatalytic decaging on cell surfaces, allowing selective cell tagging in cell mixture and tumor xenografts. Furthermore, we combined quinone methide decaging chemistry with the photocatalytic system to achieve spatially resolved membrane proteome profiling, revealing potential protein clusters. Finally, we expanded our strategy to photocatalytic prodrug decaging for selective tumor cell killing.