Simultaneously Enhancing NIR‐II Emission, Type‐I, and Type‐II Photosensitization Through Acceleration of Charge‐Separated‐State Formation for Tumor Phototheranostics

Phototheranostic agents with near-infrared (NIR) excitation wavelengths offer significant promise for tumor imaging and therapy. However, due to the limitations imposed by the energy gap law, such agents tend to generate heat while exhibiting limited photosensitization effects and fluorescence intensity, which hampers their combination therapy efficacy. Herein, we present an effective strategy of "acceleration of charge-separated-state formation" to simultaneously enhance NIR-II emission, type-I and type-II photosensitization efficiencies of NIR excitable phototheranostic agents. Specifically, following the optimization of the chemical structure and aggregated architecture, the rate of transition from localized excited (LE) state to charge-separated (CS) state is improved from 1.19 × 10⁹ s^-1 (in toluene) and 2.65 × 10¹¹ s^-1 (in water) for 8TP-IF to 4.69 × 10⁹ s^-1 (in toluene) and 1.45 × 10¹² s^-1 (in water) for 6TP-IH. As a consequence, upon NIR 808 nm excitation, the fluorescence, •OH and ¹O₂ generation efficiencies of 6TP-IH are improved to 15.6, 2.21, and 3.38 times to those of 8TP-IF. Encapsulation of 6TP-IH into nanoparticles (NPs) enables their application in NIR-II fluorescence image-guided tumor combination therapy. Both in vitro and in vivo studies confirm the precise tumor imaging capability of 6TP-IH NPs, along with robust tumor ablation and effective activation of tumor immunogenic cell death (ICD) through synergistic photodynamic and photothermal therapy. These effects collectively yield an impressive tumor inhibition rate of 99.1% in a 4T1 tumor-bearing mouse model.