“Dual Lock‐and‐Key”‐Controlled Nanoprobes for Ultrahigh Specific Fluorescence Imaging in the Second Near‐Infrared Window

Fluorescence imaging in the second near‐infrared window (NIR‐II) is a new technique that permits visualization of deep anatomical features with unprecedented spatial resolution. Although attractive, effectively suppressing the interference signal of the background is still an enormous challenge for obtaining target‐specific NIR‐II imaging in the complex and dynamic physiological environment. Herein, dual‐pathological‐parameter cooperatively activatable NIR‐II fluorescence nanoprobes (HISSNPs) are developed whereby hyaluronic acid chains and disulfide bonds act as the “double locks” to lock the fluorescence‐quenched aggregation state of the NIR‐II fluorescence dyes for performing ultrahigh specific imaging of tumors in vivo. The fluorescence can be lit up only when the “double locks” are opened by reacting with the “dual smart keys” (overexpressed hyaluronidase and thiols in tumor) simultaneously. In vivo NIR‐II imaging shows that they reduce nonspecific activitation and achieve ultralow background fluorescence, which is 10.6‐fold lower than single‐parameter activatable probes (HINPs) in the liver at 15 h postinjection. Consequently, these “dual lock‐and‐key”‐controlled HISSNPs exhibit fivefold higher tumor‐to‐normal tissue ratio than “single lock‐and‐key”‐controlled HINPs at 24 h postinjection, attractively realizing ultrahigh specificity of tumor imaging. This is thought to be the first attempt at implementing ultralow background interference with the participation of multiple pathological parameters in NIR‐II fluorescence imaging.