Biomarker-Gated Photocatalysis Uncaging in Live System

Spatiotemporal precision in photocontrolled biochemical reactions remains a central challenge. We report a sequential activation platform that integrates biomarker-triggered unlocking of photocatalyst activity with photocatalytic bioorthogonal uncaging, designed to enhance bioimaging and enable AND-gate therapeutics. By engineering diiodo-BODIPY carboxylic acid-an organic photocatalyst enabling efficient azide-to-amine reduction under light-we masked its carboxyl group as an ester to completely suppress photocatalytic activity. Strategic incorporation of enzyme- or ROS-cleavable self-immolative linkers restored catalysis in response to nitroreductase (NTR) or H₂O₂, respectively. This "lock-and-key" mechanism enables two primary functionalities: enhanced bioimaging through signal amplification by biomarker-activated BODIPY catalysts, and an "AND-gate" therapeutic activation requiring both NTR presence and light exposure for the release of caged therapeutic agents like RNase A or doxorubicin. Our platform integrates bioresponsive chemistry with light-mediated control, offering a blueprint for logical gate-regulated cellular processes and advancing precision medicine with potential for more targeted and efficient therapies.