Near-infrared (NIR) light activatable photosensitizers (PSs) garnered tremendous interest as PSs for photodynamic therapy (PDT) due to the deeper tissue penetration ability and least toxicity of NIR radiation. However, low reactive oxygen species (ROS) production, poor tumor accumulation, and residual toxicity of PSs pose major challenges for further development in this regime. In this regard, we meticulously designed and synthesized two novel mitochondria-targeted 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 ultra-low power intensity (2 mW/cm2). At higher power irradiation (100 mW/cm2), the reactive oxygen species (ROS) production by Ir2@hcy is augmented. The elevated levels of ROS disintegrate 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 in vitro and 3D tumor spheroid models, offering a new avenue to develop combinational phototherapy (PDT+PACT) for cancer treatment with spatio-temporal precision.
