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

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.