An endoplasmic reticulum and lipid droplets dual-localized strategy to develop small molecular photosensitizers that induce ferroptosis during photodynamic therapy.

Organelle-localized photosensitizers have been well-developed to enhance the photodynamic therapy (PDT) efficacy through triggering given cell death. The endoplasmic reticulum (ER) and lipid droplets (LDs) are two key organelles mutually regulating ferroptosis. Thus, in this study, small molecular photosensitizer CAR PSs were developed through fragment integration strategy and the heavy-atom modification. It was showed that the integration strategy did not affect the organelle localization and CAR PSs successfully achieved ER/LDs dual location. Besides, the heavy-atom modification help CAR PSs display good ROS generation efficiency. Importantly, ER/LDs dual-localized CAR PSs exhibited superior photo-toxicity and lower dark-toxicity against multiple breast cancer cell lines than the only ER-targeting Ce6, which further explained the superposition effect of dual organelle targeting. Preliminary studies revealed that CAR PSs induced enhanced ferroptosis via simultaneously triggering the ER stress and lipid peroxidation during PDT. Moreover, CAR-2 demonstrated significant in vivo PDT activity to suppress the tumor growth in 4T1 tumor bearing mice. These findings not only provide a promising photosensitizer CAR-2 exerting excellent in vitro and in vivo PDT effect through stimulating ferroptosis, but also propose a design strategy for the development of ER/LDs dual localized PSs.