AIEgen-Type Near-Infrared Phosphorescent Ir(III) Complex Enables Mitochondrial GSH Depletion-Amplified Photodynamic Therapy

Glutathione (GSH), the most abundant intracellular thiol-containing antioxidant, plays a pivotal role in cellular metabolism and redox homeostasis. Its critical involvement in cancer and neurodegenerative diseases has made it an important target for thiol detection systems. In this work, we report the design and synthesis of two novel near-infrared (NIR) phosphorescent Ir(III) complexes as multifunctional probes for GSH detection and photodynamic therapy (PDT). These probes feature an α,β-unsaturated ketone moiety that selectively reacts with the thiol group in GSH, enabling the specific sensing of intracellular and extracellular GSH with applications in bioimaging. Beyond their sensing capabilities, both Ir(III) complexes exhibit strong reactive oxygen species (ROS) generation efficiency, aggregation-induced emission (AIE) characteristics, and mitochondria-targeting properties, making them highly effective for PDT. Notably, upon cellular uptake, these complexes deplete mitochondrial GSH, disrupting redox homeostasis and triggering a rapid accumulation of localized ROS. This dual mechanism─combining GSH depletion and enhanced ROS production─induces potent apoptotic cell death. This work provides a strategic approach for developing advanced NIR photosensitizers with AIE activity, mitochondria-specific targeting, and the ability to simultaneously engage type I and type II PDT pathways while modulating intracellular antioxidant defense systems. Such multifunctional theranostic probes offer considerable potential for enhancing the efficacy of photodynamic cancer therapy, particularly in the treatment of hypoxic tumors.