Lysosome-targeted Ru(ii) complexes as oncosis inducers for boosting photodynamic anticancer therapy

Abstract

The development of oncosis inducers has been proposed as a promising strategy for cancer therapy, owing to their potential to avoid drug resistance and activate antitumor immune responses. Herein, we developed two lysosome-targeted oncosis inducers based on Ru(II) complexes (Ru1 and Ru2) with different ancillary ligands for photodynamic anticancer therapy, which exhibited excellent lysosome-targeting capabilities, high singlet oxygen quantum yields and enhanced photodynamic therapy (PDT) activities under acidic conditions. The Ru(II) complexes, acting as pH-responsive photosensitizers (PSs), could selectively target lysosomes, disrupt their membrane integrity, and induce the release of lysosomal contents into the cytoplasm. With the depletion of ATP and the release of Ca²⁺ from lysosomes into the cytoplasm, oncosis-specific proteins such as porimin and calpain are activated, ultimately leading to oncotic cell death. The photodynamic antitumor efficacy of the Ru(II) complexes was comprehensively assessed through in vitro studies, cellular assays, and a 4T1 tumor-bearing mouse model. Interestingly, Ru2 could selectively target and kill cancer cells under light irradiation while exerting minimal effects on normal cells. This research not only offers valuable theoretical insights into designing highly efficient PSs to enhance the effectiveness of PDT but also proposes a strategy for developing oncosis inducers through lysosomal damage.