Mitochondria/RNA cascade-targeted and fluorescence-switchable photosensitizer for photodynamic therapy augmentation and real-time efficacy self-monitoring

The localization of photosensitizers and timely efficacy evaluation highly affect efficiency of photodynamic therapy (PDT) and the resistance of residual tumor cells. Mitochondria-targeted PDT is an effective modality; however, it may encounter certain resistance caused by autophagy, a cytoprotective manner competing with cell apoptosis. Mitochondria and RNA interact closely in cell apoptosis and autophagy processes. Here, a multifunctional photosensitizer ( M1 ) is developed for cascade mitochondria- and RNA-targeted PDT and efficacy self-monitoring. It possesses the capabilities of radical reactive oxygen species generation and migration from mitochondria to RNA in cells accompanied by fluorescence turn-on during PDT. The subsequent RNA targeting by M1 can suppress autophagy and promote mitochondria-mediated cell apoptosis. Moreover, with RNA-specific switch-on and photostable fluorescence, M1 can also be used for real-time monitoring therapeutic responses of PDT. Our study provides insights into the mechanism and regulation of cell apoptosis, autophagy, and PDT resistance by a cascade-binding photosensitizer, inspiring the design of multi-targeted and fluorescence-switchable single-molecule photosensitizers. • A novel photosensitizer ( M1 ) for cascade-targeted photodynamic therapy is developed. • M1 can produce hydroxyl radical and migrate from mitochondria to RNA. • The subsequent RNA targeting can suppress autophagy and promote apoptosis. • RNA-specific switch-on fluorescence facilitates real-time efficacy monitoring.