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.

光敏剂的定位和及时的疗效评估高度影响光动力疗法（PDT）的效率和残留肿瘤细胞的抵抗力。线粒体靶向 PDT 是一种有效的方式；然而，它可能会遇到由自噬引起的某些抵抗，自噬是一种与细胞凋亡竞争的细胞保护方式。线粒体和 RNA 在细胞凋亡和自噬过程中密切相互作用。在这里，开发了一种多功能光敏剂 ( M1 )，用于级联线粒体和 RNA 靶向 PDT 和功效自我监测。它具有在细胞中产生自由基活性氧和从线粒体迁移到 RNA 的能力，并在 PDT 期间伴随荧光开启。随后通过M1靶向 RNA能抑制自噬，促进线粒体介导的细胞凋亡。此外，通过 RNA 特异性开启和光稳定荧光，M1还可用于实时监测 PDT 的治疗反应。我们的研究提供了对级联结合光敏剂对细胞凋亡、自噬和 PDT 抗性的机制和调节的见解，启发了多靶点和荧光可切换的单分子光敏剂的设计。