Photoswitchable imaging contrast agents as an emerging frontier in precision bioimaging

Photoswitchable molecules exhibit reversible photoisomerization between distinct isomeric states under alternating light irradiation, possessing unique photophysical properties. Derived from these molecules, photoswitchable imaging contrast agents (PICAs) offer significant advantages over conventional agents: (1) background suppression through state-switching algorithms; (2) continuous imaging capability enabled by high fatigue resistance; (3) rapid signal modulation minimizing acquisition time. A comprehensive analysis of PICA advancements and persistent challenges across bioimaging applications is imperative. This review systematically evaluates several representative photoswitchable molecules as PICAs and proposes innovative molecular design and assembly strategies to address the limitations hindering the widespread implementation of PICAs in bioimaging, such as hydrophobicity, short-wavelength excitation, and suboptimal emission performance. Additionally, recent advances in PICAs for fluorescence, phosphorescence, photoacoustic, magnetic resonance and Raman imaging are summarized, highlighting their significant contributions to improving bioimaging quality and precision. Finally, an outlook is provided on the intersection of PICA design and property optimization for propelling both preclinical physiological research and clinical diagnostic and monitoring technologies.