Activatable Molecular Probes With Clinical Promise for NIR‐II Fluorescent Imaging

Abstract The second near‐infrared window (NIR‐II) fluorescence imaging has been widely adopted in basic scientific research and preclinical applications due to its exceptional spatiotemporal resolution and deep tissue penetration. Among the various fluorescent agents, organic small‐molecule fluorophores are considered the most promising candidates for clinical translation, owing to their well‐defined chemical structures, tunable optical properties, and excellent biocompatibility. However, many currently available NIR‐II fluorophores exhibit an “always‐on” fluorescence signal, which leads to background noise and compromises diagnostic accuracy during disease detection. Developing NIR‐II activatable organic small‐molecule fluorescent probes (AOSFPs) for accurately reporting pathological changes is key to advancing NIR‐II fluorescence imaging toward clinical application. This review summarizes the rational design strategies for NIR‐II AOSFPs based on four core structures (cyanine, hemicyanine, xanthene, and BODIPY). These NIR‐II AOSFPs hold substantial potential for clinical translation. Furthermore, the recent advances in NIR‐II AOSFPs for NIR‐II bioimaging are comprehensively reviewed, offering clear guidance and direction for their further development. Finally, the prospective efforts to advance NIR‐II AOSFPs for clinical applications are outlined.