“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

Abstract Conventional cyanine dyes with a symmetric structure are “always‐on”, which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR‐II non‐symmetric cyanine (NSCyanine) dyes by harnessing a non‐symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a “dual‐key‐and‐lock” strategy. These NSCyanine dyes with a low p K a (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target‐to‐liver ratios up to 19.5/1. Notably, high‐contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis‐imaging, acute gastritis‐imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.