Engineering water-soluble photoswitches: design strategies and biological applications for spatiotemporal control.

Molecular photoswitches enable precise, non-invasive remote control of biological processes with high spatiotemporal resolution, yet their biological translation remains severely constrained by poor water solubility. Therefore, engineering water-soluble photoswitches has become a critical prerequisite for advancing light-controlled technologies toward biological applications. In this review, we first summarize the molecular design strategies that render hydrophobic photoswitches water-soluble, categorizing current approaches into covalent modification and non-covalent assembly. We then highlight state-of-the-art biological applications of water-soluble photoswitches, including bioimaging, super-resolution imaging, photopharmacology, photocontrolled photodynamic therapy and drug delivery. Finally, we discuss the opportunities and remaining challenges in developing next-generation water-soluble photoswitches, and outline future directions toward intelligent, bio-compatible, and clinically translatable photoswitchable systems.