A near-infrared aggregation-induced emission photosensitizer with mitochondria specificity enhances radiotherapy for cancer stem cells ablation

Multifunctional fluorescent molecules with organelle-targeting capabilities and high phototherapeutic efficacy have been regarded as promising materials for real-time tumor diagnosis and non-invasive treatment in the clinic. In this study, we developed a near-infrared (NIR) emissive photosensitizer, DACNPy+, which exhibits mitochondrial targeting ability, laser-triggered type I and type II reactive oxygen species (ROS) generation, and aggregation-induced emission (AIE) properties. After being encapsulated by platelet membranes and liposomal membranes, DACNPy+ was formulated into biomimetic nanoparticles termed DFL, which demonstrated remarkable tumor-targeting capabilities and <i>in vivo</i> long-term tumor tracking. Upon laser irradiation, DFL disintegrated within the lysosomes of cancer cells, releasing DACNPy+ and target mitochondria, thereby achieving mitochondria-targeted photodynamic therapy (PDT). This process resulted in mitochondrial dysfunction and disruption of cellular homeostasis. Notably, the highly efficient PDT successfully sensitized radiotherapy, forming a synergistic therapeutic system with "1 + 1 > 2" effect for effective killing of cancer stem cells and tumor ablation. This work offers a novel alternative to traditional clinical theranostics strategies.