Cascade Responsive Photosensitizer for Precise Delivery and Photodynamic Therapy.

We report a tumor microenvironment-responsive photosensitizer (1) as a molecular chameleon with cascade transformation capabilities for precision-controlled photosensitizer delivery. 1 is encapsulated in a pH-responsive surfactant to form 1a 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 2 through an aromatic nucleophilic substitution. This transformation of hydrophobic 1 to hydrophilic 2 leads to the release of photosensitizer with size reduction, potentially enhancing drug accumulation and facilitating tumor penetration. Furthermore, after treatment, 2 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 1a 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.