Abstract
Carbon-centered radicals offer unmatched nanometer-scale precision for proximity
labeling, yet existing light-driven platforms such as μMap are limited by shallow
tissue penetration and phototoxicity. We present the first fully light-free, dualluciferase BRET system that redefines in vivo proximity proteomics. A bespoke Ir(III)
photocatalyst-[Ir(dF(CF₃)ppy)₂(bpy-N₃-maleimide)]PF₆ is site-specifically tethered to
both EGFR-targeting antibodies and luciferases (NanoLuc or RLuc8.6-535), placing
the catalyst and donor within 10 nm for on-demand single-electron transfer. This
architecture generates high-efficiency carbon radicals deep within tissue (>3 mm)
without any external light source, eliminating phototoxicity while preserving
nanometer spatial resolution. By leveraging NanoLuc’s intense emission and
RLuc8.6-535’s spectral isolation, we achieve unprecedented signal-to-noise ratios
and proteome coverage—unlocking a truly in vivo-compatible route for spatially
resolved microenvironment mapping.
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