A light-gated "membrane-to-mitochondria" sequentially targeted AIE photosensitizer for potentiated photodynamic therapy and imaging of breast cancer.

Precision photodynamic therapy (PDT) requires efficient and selective subcellular organelle targeting to maximize antitumor efficacy while minimizing systemic toxicity. Herein, we developed a cationic photosensitizer, TBP-EQ, bearing a terminal quaternary ammonium group for light-triggered "plasma membrane-to-mitochondria" targeting. Unlike its mitochondrial-localized analogue TBP-E, TBP-EQ preferentially anchors on the cancer cell plasma membrane through enhanced electrostatic interactions. Upon light irradiation, TBP-EQ generates reactive oxygen species (ROS) in situ at the plasma membrane, inducing oxidative membrane damage and increasing membrane permeability, which in turn promotes its intracellular translocation and subsequent mitochondrial enrichment. This light-controlled sequential targeting strategy enables combined damage to both the plasma membrane and mitochondria, thereby amplifying photodynamic antitumor efficacy. In vivo investigations using a murine tumor model demonstrated that TBP-EQ exhibited prolonged tumor retention and achieved a high tumor inhibition rate of 97.5%, together with an excellent systemic safety profile. This work proposes a spatiotemporally regulated subcellular targeting strategy, providing a feasible approach for the development of high-performance precision photosensitizers.