A CYP2J2‐Activated Photosensitizer with In Situ Enzyme Anchoring Induces Pyroptosis in Cancer Therapy

Abstract In photodynamic therapy, traditional photosensitizers exhibit limited tumor retention and targeting efficiency, posing significant challenges to achieving precision and efficacy. In this study, a photosensitizer is developed based on a hemicyanine dye, known as Icy‐P, which features a cationic structure that naturally targets mitochondria. Icy‐P contains CYP2J2 recognition receptors at its active sites, enabling precise targeting of tumor cells. Positioning ethyl carbamate adjacent to the recognition group of Icy‐P initiates a cascade reaction upon CYP2J2 recognition, resulting in the formation of a quinone intermediate, which undergoes a 1,4‐addition reaction. This reaction facilitates the binding of Icy‐P to an enzyme, leading to a prolonged retention time. The in vivo residence time of Icy‐P within tumor cells ranges between 48 h and 7 d. Furthermore, Icy‐P generates reactive oxygen species upon light exposure, leading to mitochondrial damage, caspase‐1 activation, and gasdermin D cleavage. These events ultimately induce pyroptosis, thereby enhancing the efficacy of cancer therapy.