Enabling Proteins with Photocatalytic Functions via HisTag–Iridium Coordination

The ability to endow proteins with new chemical reactivities is central to expanding their functional repertoires in chemical biology and therapeutics. However, the construction of protein-photocatalyst systems typically demands extensive genetic or synthetic manipulation. Here, we report a minimal and modular strategy that enables the <i>in situ</i> formation of iridium-based photocatalysts through HisTag-iridium coordination, termed CAT-tag. By leveraging the ubiquitous HisTag, nonphotoactive Ir(III) precursors are spontaneously converted into luminescent and photocatalytic complexes under mild aqueous conditions. The resulting His-anchored photocatalytic proteins display robust photocatalytic activity across representative protein scaffolds, including nanobodies and therapeutic antibodies. We further demonstrate the functional versatility of the CAT-tag in conjunction with photocatalytic reactions, enabling spatially resolved surfaceome labeling, dynamic cell-cell interaction mapping, and targeted prodrug activation in living systems. As most recombinant proteins inherently contain a terminal HisTag, the CAT-tag requires no additional genetic modification and installs photocatalytic activity through a single coordination-driven step. This remarkable operational simplicity underscores the power and elegance of chemical strategies in protein engineering. By repurposing the HisTag, one of the most ubiquitous and accessible motifs in protein science, the CAT-tag transforms a routine biochemical handle into a chemically programmable interface for light-driven protein functionalization and biological interrogation.