A Dual‐Locked and H 2 S‐NO Tandem‐Activatable NIR‐II Nanoagent for Colon Cancer Theranostics

ABSTRACT Dual‐locked activatable theranostics have been emerging as a promising cancer therapy platform. However, most of the reported dual‐locked systems only restricted to enzyme‐responsive probes, new molecular tools with other biomarker‐responsiveness still remain challenging. Moreover, optical manipulation in the second near‐infrared (NIR‐II) window can potentially boost the theranostic efficacy, but having rarely been explored. In this study, we report a dual‐locked and gas tandem‐activatable NIR‐II nanoagent for colon cancer theranostics. Water‐dispersible nanoparticles containing a nitrated organic small molecule (CTBN) and an acid‐responsive NO donor (NONOate; CTBNN‐NPs) are fabricated, displaying negligible emission in visible‐NIR region. Upon uptake by colon cancer cells, CTBNN‐NPs can be tandemly activated by the overexpressed H 2 S and the in situ released NO, thus turning on NIR‐II emission extending to 1200 nm. Moreover, the activated CTBNN‐NPs also demonstrate augmented NIR absorption as well as robust photothermal and type‐I photodynamic performance, achieving NIR‐II fluorescence imaging‐guided efficient photo‐elimination of colon cancer together with NO gas therapy, while exhibiting limited efficacy in the tested cervical and breast cancer models. This work provides a new molecular design approach to dual‐locked and H 2 S‐NO tandem‐activatable nanoagents with gas‐responsive and NIR‐II active capabilities, highlighting the exciting potential for cancer theranostics.