Halogen-modified photosensitizers: Inducing mitochondrial dysfunction for tumor suppression.

The rational design of halogenated organic photosensitizers (PSs) to optimize their tumor therapeutic performance remains a significant challenge. Herein, we constructed two PSs (LYD-F and LYD-Br) with identical molecular skeleton but distinct terminal halogens (F vs. Br) to directly compare their tumor therapeutic performance. Spectroscopic characterization revealed that LYD-F possesses a superior molar extinction coefficient (ε = 1.75 × 10⁵ M⁻¹ cm⁻¹) compared to LYD-Br (ε = 1.67 × 10⁵ M⁻¹ cm⁻¹). Both PSs were subsequently nano-formulated using DSPE-PEG2000. Under 808 nm laser irradiation, LYD-F nanoparticles (LYD-F NPs) demonstrated exceptional photothermal performance, achieving a rapid temperature increase (ΔT = 43.83 °C) and a high photothermal conversion efficiency (PCE = 62.39%), outperforming LYD-Br nanoparticles (LYD-Br NPs) (ΔT = 38.76 °C, PCE = 55.02%). Moreover, LYD-F NPs exhibited a remarkable reactive oxygen species (ROS) generation capability, producing higher ROS than LYD-Br NPs. Given LYD-F NPs superior photophysical properties, LYD-F NPs were selected for further anti-tumor evaluation. LYD-F NPs + Laser effectively induced mitochondrial damage, leading to potent tumor ablation. Notably, the treatment also triggered immune response, significantly suppressing tumor lung metastasis. This study compared the performance of fluorinated and brominated photosensitizers (LYD-F and LYD-Br), confirming that introducing fluorine atoms into photosensitizers (PSs) is an ideal design strategy for performance optimization.