An octupolar donor-acceptor dye exploiting aggregation-induced intersystem crossing for efficient ROS generation

Photodynamic therapy (PDT) requires photosensitizers (PSs) that efficiently generate reactive oxygen species (ROS) or otherwise induce cell damage, even under the hypoxic conditions typical of solid tumor environments. Here, we report a heavy-atom-free octupolar donor-acceptor dye, 3CN, designed with a triphenylamine core and three cyanovinyl-benzothiazole acceptors. This dye harnesses aggregation-induced intersystem crossing (AI-ISC) to promote efficient triplet state population. In aqueous solutions, 3CN spontaneously self-assembles into stable nanoaggregates (3CNAgg) that exhibit excellent colloidal stability and prolonged triplet-state lifetimes. These aggregates demonstrate superior Type I photosensitization capabilities, generating the superoxide anion radical (O₂˙^-) with significantly greater efficiency under white light irradiation than the reference PS, rose bengal. In encapsulated formulation, 3CNEn, exhibits remarkable therapeutic efficacy with IC₅₀ values of 8.6 μM against triple-negative human breast cancer cells (MDA-MB-231), while maintaining potent photocytotoxicity even under severely hypoxic conditions (1% O₂). In vivo studies using mouse models bearing MDA-MB-231 tumors demonstrate 100% inhibition of tumor growth with minimal dark cytotoxicity and inherent tumor-targeting properties.