Harnessing Hypoxia‐Dependent Cyanine Photocages for In Vivo Precision Drug Release

Photocaging holds promise for the precise manipulation of biological events in space and time. However, current near‐infrared (NIR) photocages are oxygen‐dependent for their photolysis and lack of timely feedback regulation, which has proven to be the major bottleneck for targeted therapy. Herein, we present a hypoxia‐dependent photo‐activation mechanism of dialkylamine‐substituted cyanine (Cy‐NH) accompanied by emissive fragments generation, which was validated with retrosynthesis and spectral analysis. For the first time, we have realized the orthogonal manipulation of this hypoxia‐dependent photocaging and dual‐modal optical signals in living cells and tumor‐bearing mice, making a breakthrough in the direct spatiotemporal control and in vivo feedback regulation. This unique photoactivation mechanism overcomes the limitation of hypoxia, which allows site‐specific remote control for targeted therapy, and expands the photo‐trigger toolbox for on‐demand drug release, especially in a physiological context with dual‐mode optical imaging under hypoxia. We present a hypoxia‐dependent cyanine photolysis mechanism for controlled release. P(Cy‐N‐CPT) could realize the precise orthogonal manipulation of photocaging and dual‐modal optical signals for targeted therapy under hypoxic tumor conditions.