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.