A near-infrared aggregation-induced emission photosensitizer targeting mitochondria for depleting Cu2+ to trigger light-activated cancer cells oncosis

Schematic illustration of photodynamic therapy of TTQ-Th to accelerate ablating cancer cells. [Display omitted] •Altering functional group of compounds enhances the ability to target mitochondria.•TTQ-Th has desirable advantage of large stokes shifts and bright NIR emission.•The sufficient ROS generation of TTQ-Th upon photoexcitation can ablate cancer cells.•TTQ-Th inhibit copper-based enzyme activity to suppress metastasis of cancer cells. Abnormally high levels of copper in tumors stimulate malignant proliferation and migration of cancer cells, which proposes a formidable challenge for the thorough therapy of malignant tumors. In this work, we developed a reliable, mitochondria-targeted near-infrared aggregation-induced emission fluorescent probe, TTQ-Th, whose thiourea moiety specifically could recognize mitochondria even both upon loss of mitochondrial membrane potential or in fixated cells, and can capture copper overexpressed by tumor cells, leading to severe copper deficiency. In parallel, TTQ-Th can generate sufficient reactive oxygen species (ROS) upon photoexcitation, while copper deficiency inhibits expression of related copper-based enzymes, resulting in a decline in ATP production. Such energy deficiency, combined with reduced MMP and elevated oxidative stress can lead to critical cell oncosis. Both in vitro and intracellular experiments can illustrate that the elevated ROS has remarkable damage to tumor cells and contributes to the elimination of the primary tumor, while copper deficiency further hinder tumor cell migration and induces G0/G1 cell cycle arrest in a dose-dependent manner, which is an efficacious strategy for the treatment of malignant tumors.