Cascade Responsive Photosensitizer for Precise Delivery and Photodynamic Therapy

We report a tumor microenvironment-responsive photosensitizer (<b>1</b>) as a molecular chameleon with cascade transformation capabilities for precision-controlled photosensitizer delivery. <b>1</b> is encapsulated in a pH-responsive surfactant to form <b>1a</b> with a PEGylated surface that does not generate ROS in normal tissues. The ROS generation is activated by the overexpressed glutathione at the acidic tumor site to yield <b>2</b> through an aromatic nucleophilic substitution. This transformation of hydrophobic <b>1</b> to hydrophilic <b>2</b> leads to the release of photosensitizer with size reduction, potentially enhancing drug accumulation and facilitating tumor penetration. Furthermore, after treatment, <b>2</b> is deactivated by γ-glutamyl transferase through specific hydrolysis and intramolecular rearrangement reactions, thereby reducing the potential undesired phototoxicity. In vitro and in vivo studies show that is deactivated by γ-glutamyl transferase through specific hydrolysis and intramolecular rearrangement reactions, thereby reducing the potential undesired phototoxicity. In vitro and in vivo studies show that <b>1a</b> affords excellent phototoxicity to cancer cells by the pyroptosis pathway. This work offers a promising strategy to design molecular chameleons to control spatiotemporal delivery of photosensitizes and to enhance the photodynamic therapy efficacy.