Biomarker‐Gated Photocatalysis Uncaging in Live System

Abstract 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 H 2 O 2 , 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.