A Long-Term Plasma Membrane-Anchored Photosensitizer for Pyroptosis-Induced Anticancer Therapy.

The development of precise and stable membrane-anchoring photosensitizers is important but challenging for pyroptosis-mediated antitumor therapy. Here, we report a tumor cell membrane-anchored BODIPY photosensitizer (TPMS) capable of inducing plasma membrane rupture via the pyroptosis pathway. Its modular structure integrates a BODIPY core and phenothiazine unit to boost reactive oxygen species (ROS) generation, a quaternary ammonium salt for membrane anchoring, and a disulfide bridge for covalent immobilization. In aqueous solution, TPMS self-assembles into nanoaggregates with intense absorption at 658 nm and efficient type-I ROS production. Notably, TPMS was covalently immobilized on plasma membranes with a prolonged retention time of at least 2 h and effectively induced pyroptosis of cancer cells upon light irradiation. Furthermore, in vivo studies confirmed its potent tumor eradication efficacy with minimal systemic toxicity. This work not only provides a rational molecular strategy for constructing long-term membrane-localized photosensitizers but also highlights the potential of pyroptosis-mediated anticancer treatment.