Dissecting Mitochondrial Sulfur Dioxide Generation Mechanism in Rheumatoid Arthritis with a NIR Luminogenic Iridium(III)-Based Probe

Sulfur dioxide (SO2), a gaseous signaling molecule that can be produced endogenously in mitochondria, is an important antioxidant for maintaining redox homeostasis. Abnormal levels of mitochondrial SO2 are associated with the pathogenesis and progression of rheumatoid arthritis (RA). Therefore, it is crucial to develop a luminescence probe that can detect subcellular SO2 levels for unmasking the pathological changes and diagnosis of RA. However, current luminescence probes for SO2 in RA suffer from low photostability, weak response, short emission wavelengths below 650 nm, and/or poor mitochondria targetability. In this work, we developed a near-infrared (NIR) iridium(III) complex-based probe based on the Michael addition mechanism for rapid, real-time, and accurate detection of mitochondrial SO2. The probe not only achieved sensitive detection of SO2 in aqueous solution with a detection limit of 2.12 μM but also imaged endogenous mitochondrial SO2 levels in a cellular RA model. Furthermore, it visualized aspartate aminotransferase 1 (AAT1)-mediated SO2 generation, offering insight into the mechanism of SO2 generation in RA. Finally, it also exhibits an excellent penetration capability within 3D tumor spheroids (approximately 103 μm). Overall, this probe offers a powerful tool for effectively imaging subcellular SO2 in RA, thereby enhancing our understanding of the pathological mechanisms of RA and accelerating the development of diagnostic tools for RA.