An AIE-active type I/II photosensitizer with mitochondria-to-nuclei cascade targeting for highly efficient photodynamic cancer therapy

photodynamic therapy (PDT) has emerged as a prominent strategy for the treatment of breast Cancer, which is prevalent among women globally. Organelles targeted photosensitizers have brought great promise for enhancing the PDT efficiency. Photosensitizers possessing mitochondria and nuclei dual-targeting, especially those multipled with type I/II Reactive Oxygen Species (ROS) generation and aggregation-induced emission (AIE) characteristics are urgently needed to improve the PDT efficiency. Herein, a new amphiphilic compound, 2-(2-(5-(7-(4-((4-butylphenyl)(4-(7-(5-formylthiophen-2-yl)benzo[c] [1,2,5]thiadiazol-4-yl)phenyl)amino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)vinyl)-3-methylbenzo[d]thiazol-3-ium iodide (SgTBB), is introduced. SgTBB exhibits bright emission at 731 nm in solution and it redshifts to 930 nm in solid state. Interestingly, SgTBB generates singlet oxygen (¹O₂, type II ROS) and •OH/O₂ ^-• (type I ROS) simultaneously when exposed to light irradiation. In vitro experiments show that SgTBB NPs can light up the cells and exhibit light-driven mitochondria-to-nuclei cascade targeting. Under light irradiation, decrease of mitochondrial membrane potential (MMP), obvious mitochondria damage, upregulation of cleaved Caspase-3 expression as well as severe DNA damage are observed, which further cause cell Apoptosis and immunogenic cell death (ICD), then promote the antitumor activity. Furthermore, SgTBB NPs used as a phototheranostic agent can effectively inhibit tumor growth in mice. Our research demonstrates that SgTBB NPs can be used as a potent Photosensitizer for imaging-guided PDT, and the work here presents a wonderful route for the creation of multi-organelles targeted photosensitizers with special type I/II ROS generation capability.

Aggregation-induced emission; DNA damage; Mitochondria-to-nuclei targeting; Photodynamic therapy; Type I/II photosensitizer.