Hydrazone-based photocages for precise sub-organelle visualization and drug release

Photocages are widely investigated for their bioimaging, controlled drug release, and cellular process modulation. Developing universal photoactive units can significantly expand the structural diversity of photocages. Herein, we developed a class of photoactive units based on the classic aldehyde-hydrazone moiety by conjugating several fluorescent aldehydes with various substituted phenylhydrazines. The resulting hydrazone-based photocages degraded upon exposure to light (365-450 nm), releasing fluorescent aldehydes. Fluorescent enhancements, redshifts or blueshifts were clearly observed during uncaging. For bio-application, morpholine-hydrazone based hybrid BW3MP, staurosporine-derived hybrids BW3STS and FY4STS were constructed. They exhibited high release efficiencies of MP (75.5%, BW3MP) and STSA (65.3%, BW3STS), respectively. BW3MP co-localized with a lysosome dye, exhibiting a Pearson correlation coefficient of 0.94. The biological activity of BW3STS was unmasked under irradiation, with a 4-fold increase in IC₅₀. Our work developed photoactive units that hold significant promise for the constitution of general suitable drug delivery systems (DDSs).