CAIX-targeted red-light-activated osmium(II) polypyridyl photosensitizer inducing pyroptosis and ferroptosis to combat hypoxia tumors.

To overcome the limitations imposed by hypoxia in photodynamic therapy (PDT), we rationally designed and synthesized three carbonic anhydrase IX (CAIX)-targeted osmium(II) polypyridyl complexes (Os1-Os3) by conjugating a benzenesulfonamide CAIX inhibitor to the photosensitizer core. Among them, Os3 exhibited excellent photophysical properties and efficient singlet oxygen generation. This complex showed remarkable selectivity for CAIX-overexpressing MDA-MB-231 cancer cells, with very low dark toxicity (IC50 > 100 μM) and outstanding phototoxicity (IC50 = 2.2 μM, phototoxicity index = 45) upon red light irradiation (633 nm, 15 mW cm-2). Mechanistic studies revealed that upon illumination at 633 nm (15 mW cm-2), Os3 induced the generation of reactive oxygen species (ROS), which subsequently led to a decrease in mitochondrial membrane potential and reduced ATP production. Further investigations showed that Os3-mediated PDT triggered upregulation of the GSDMD-N protein, increased malondialdehyde (MDA) levels, and downregulation of GPX4 protein expression. Collectively, these results indicate that Os3-mediated PDT exerts its anticancer effects by inducing pyroptosis, and ferroptosis. In vivo, Os3-PDT significantly suppressed the growth of 4T1 tumors, achieving an inhibition rate of 58.7%. Os3 represents a CAIX-targeted osmium(II) photosensitizer that combats tumors by inducing multimodal cell death and remodeling the tumor microenvironment.