Dual‐Acceptor Engineered Multimodal Phototheranostic NIR‐II AIEgens for Orthotopic Breast Cancer Treatment

ABSTRACT “One‑for‑all” phototheranostics has emerged as a promising alternative to conventional cancer therapies. Aggregation‑induced emission luminogens (AIEgens) are exemplary templates for constructing such versatile systems. However, developing robust NIR‑II (1000–1700 nm)‐emitting “one‑for‑all” phototheranostic AIEgens remains challenging, due to the drastically lowered reactive oxygen species (ROS) generation capability and strong intermolecular π‐π stacking in the NIR‑II range. To address this, an ingenious dual‑acceptor strategy was proposed. It leverages the steric hindrance between two moderate‑strength acceptors to create a twisted dual‑acceptor configuration, which not only circumvents the detrimental effects caused by large planar strong acceptors, such as π–π stacking‐induced emission quenching and excited‐state energy loss, but also favors AIE nature. Moreover, moderate‑strength acceptors are readily functionalized, facilitating the introduction of substituents that enhance ROS performance. Through combining a strong donor, an optimized AIE small molecule, TTBI, was identified, which exhibits desirable NIR‑II emission, excellent type I ROS production, and a high photothermal conversion after formulation into nanoparticles (NPs). Coupled with outstanding stability and biocompatibility, TTBI NPs demonstrated exceptional 808 nm‑excitable NIR‐II fluorescence–photoacoustic–photothermal trimodal imaging and synergistic photodynamic–photothermal therapy in mouse orthotopic breast cancer models. This work provides new insights for creating superior NIR‑II multimodal phototheranostic agents.