TagC-RED: An Infrared-Triggered Retro-Ene Reaction for Deep-Tissue Bioconjugation

Abstract

Bioconjugation reactions are indispensable for probing biomolecules in their native environments. Photoactivatable bioconjugation offers spatiotemporal control; however, current methods face significant limitations, including the requirement for noncanonical functional groups, cytotoxic heavy-metal catalysts, and high-energy UV or visible light (λ < 800 nm), which restrict tissue penetration and increase phototoxicity risks. In response, we introduce TagC-RED, a Retro-Ene type sigmatropic rearrangement of Diazonium compounds for Cysteine-specific bioconjugation activated by infrared light (λ > 1000 nm). TagC-RED is quantitative, rapid, and catalyst-free, with deep tissue penetration, enabling robust labeling intracellularly and in vivo. Mechanistic studies and DFT calculations show that TagC-RED activates through the formation of an electron donor–acceptor (EDA) complex that enables IR irradiation and undergoes a stepwise retro-ene reaction. TagC-RED holds significant potential as a platform for in vivo chemical biology and diagnostic innovation.