Harnessing Radical-Mediated Photocaged Cyanine under Hypoxia for in vivo Precision Drug Release.

Photocaging with noninvasive nature and remote control holds promise for fine manipulation of biological events in space and time. However, current near-infrared (NIR) photocages are oxygen-dependent photolysis and lack of timely feedback regulation, proven to be the major bottleneck for targeted therapy. Herein, we discovered a radical-mediated photo-activation mechanism of dialkylamine-substituted cyanine (Cy-NH) under hypoxia accompaning with emissive fragments generation, which efficiently validated with retrosynthesis and spectral analysis. For the first time, we have realized orthogonal manipulation of this radical-mediated photocaging and dual-modal optical signals in living cells and tumor-bearing mice, making a breakthrough in directly spatiotemporal control and timely in vivo feedback regulation. This discovery of unique radical-mediated photoactivation conquers the limitation of hypoxia, allowing site-specifically remote control for targeted therapy, which paves a new way for expanding the photo-triggered toolboxes for on-demand drug release, especially in a physiological context with dual-mode optical imaging under hypoxia.