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

Persistent emission unresponsive to the microenvironment results in high background noise, low imaging contrast, and poor specificity.

“This persistent emission, which is unresponsive to the microenvironment, results in high background noise, low imaging contrast, and poor specificity88.”

NSCyanine fluorescence activation is based on dual-environmental sensitivity: it remains off at physiological pH, protonation under acidic conditions at pH 4.0-5.5 triggers weak fluorescence, and high-viscosity environments further amplify the signal up to 20-fold.

“Their fluorescence activation was based on a dual-environmental sensitivity mechanism: the dye remained in an “off” state at physiological pH, while protonation under acidic conditions (pH 4.0–5.5) triggered weak fluorescence, which was further amplified in high-viscosity environments, yielding up to a 20-fold signal enhancement.”

Xiong et al. developed a pH/viscosity-activatable NIR-II non-symmetric cyanine dye for high signal-to-background ratio theranostics within the liver in vivo.

“To address these limitations, Xiong et al. developed a pH/viscosity-activatable NIR-II non-symmetric cyanine (NSCyanine) dye, specifically engineered for high signal-to-background ratio (SBR) theranostics within the liver in vivo (Fig. 4a)88.”

The diagnostic precision of most NIR-II cyanine dyes is severely limited by their always-on fluorescence signature.

“The diagnostic precision of most NIR-II cyanine dyes is severely limited by their “always-on” fluorescence signature.”

The dual-activation mechanism of NSCyanine effectively minimized hepatic background and enhanced imaging precision.

“This dual-activation mechanism effectively minimized hepatic background and enhanced imaging precision.”

In 4T1 breast tumor models, NSCy-1050 demonstrated exceptional tumor-specific accumulation, achieving an unprecedented tumor-to-liver fluorescence ratio of 19.5:1.

“In 4T1 breast tumor models, NSCy-1050 demonstrated exceptional tumor-specific accumulation, achieving an unprecedented tumor-to-liver fluorescence ratio of 19.5:1.”

Xiong et al. developed a NIR-II theranostic agent (NSCy-1050) through covalent conjugation of a dual pH/viscosity-responsive fluorophore (NSCy-975) with water-soluble PEG-glucosamine and camptothecin (CPT).

“Xiong et al. developed a NIR-II theranostic agent (NSCy-1050) through covalent conjugation of a dual pH/viscosity-responsive fluorophore (NSCy-975) with water-soluble PEG-glucosamine and camptothecin (CPT) (Fig. 20a)88.”