Near-infrared light-activatable iridium(<scp>iii</scp>) complexes for synergistic photodynamic and photochemotherapy

Near-infrared (NIR) light-activatable photosensitizers (PSs) have garnered tremendous interest as PSs for photodynamic therapy (PDT) due to the deeper tissue penetration ability and lower toxicity of NIR radiation. However, the low reactive oxygen species (ROS) production, poor tumor accumulation, and residual toxicity of these PSs pose major challenges for further development in this regime. In this regard, we have meticulously designed and synthesized two novel mitochondria-targeting iridium(iii)-dithiocarbamate-cyanine complexes, Ir1@hcy and Ir2@hcy. In particular, Ir2@hcy exhibited both type I and type II PDT with excellent singlet oxygen (¹O₂) and hydroxyl radical (˙OH) generation ability under 637 nm/808 nm irradiation, even at an ultra-low power intensity (2 mW cm^-2). Under higher-power irradiation (100 mW cm^-2), the reactive oxygen species (ROS) production by Ir2@hcy was augmented. The elevated levels of ROS caused the disintegration of Ir2@hcy to produce cytotoxic oxindole scaffolds through the dioxetane mechanism. The synergistic production of ROS and cytotoxic species effectively induced mitochondria-mediated cancer cell death in both <i>in vitro</i> and 3D tumor spheroid models, offering a new avenue to develop combinational phototherapy (PDT + PACT) for cancer treatment with spatio-temporal precision.