A mitochondrion-targeting two-photon photosensitizer with aggregation-induced emission characteristics for hypoxia-tolerant photodynamic therapy

In recent years, two-photon photodynamic therapy (TP-PDT) has received extensive attention in cancer treatment owing to its unique advantages of deep tissue penetration and high spatial-temporal controls. However, the high oxygen dependency of photosensitizers still remained as the major obstacle which undermined its overall therapeutic efficacy, especially in hypoxic-tolerant tumors. Exploration of new TP-PDT strategy with less-oxygendependency and subcellular organelle-targeting ability is an appealing yet seriously challenging task. In this work, a mitochondrion-targeting TP-PDT protocol based on type-I PSs with aggregation-induced emission (AIE) characteristics is proposed for the first time. Of the two synthesized AIE-active PSs, TPABP-Ir is demonstrated superior reactive oxygen species (ROS) production (both type I&II) owing to the doping of Ir(III). After encapsulation into bovine serum albumin (BSA) matrix, TPABP-Ir@BSA nanoparticles (Ir-NPs) are capable of realizing mitochondrion-targeting, high ROS production, and suppression of tumor growth under 880 nm femtosecond laser excitation. This study provides a novel treatment strategy which maximizes the PDT efficacy and offers a conceptual but practical paradigm for cancer treatment in translational nanomedicine.