Switchable Nanophotosensitizers as Pyroptosis Inducers for Targeted Boosting of Antitumor Photoimmunotherapy

Photodynamic therapy (PDT) has emerged as a promising modality for cancer treatment, but its clinical application is constrained by unexpected phototoxicity arising from nonspecific photosensitizer activation and their “always-on” nature. Herein, we developed a switchable nanophotosensitizer, poly(cation−π) nanoparticles (NP), which achieves supramolecular assembly through cation−π interactions. By coupling choline cationic moieties with aromatic photosensitizers (ZnPc), the polymer facilitates self-assembly driven by cation−π interactions for NP engineering. Surprisingly, the photoactivity of ZnPc was completely quenched upon complexation via cation−π interactions, thereby significantly avoiding skin phototoxicity. Upon targeting tumor cells, NP undergoes a GSH-responsive degradation process that weakens cation−π interactions, leading to spontaneous restoration of photoactivity and amplifying tumor immunogenic pyroptosis. In vivo studies demonstrated that NP achieved a high tumor inhibition rate of 84% while effectively avoiding skin phototoxicity. This work provides a novel perspective for enhancing the safety and efficacy of PDT-based tumor treatment.