Concurrent Subcellular Delivery of Hydrogen Sulfide and a Payload with Near-Infrared Light.

Hydrogen sulfide (H2S) is a gaseous signaling molecule, exerting crucial regulatory functions in organelles and cellular environments. H2S exhibits high therapeutic potential and synergistic effects with other drugs, and its potency is notably enhanced through organelle-specific targeting. Yet, the navigation of light-activated H2S donors to specific organelles remains absent. Here, we report the first organelle-specific photocage that simultaneously delivers H2S and a payload with subcellular precision to mitochondria of live human cells using tissue-penetrating near-infrared light as a trigger. The fluorogenic payload enables real-time monitoring of the process, and we demonstrate the concurrent uncaging in mitochondria through a combination of fluorescence microscopy and mitochondria-specific fluorescent probes. We anticipate that these photocages will permit the precise delivery of H2S-drug combinations with exceptional spatiotemporal control, thereby driving the harnessing of known synergistic effects and the discovery of novel therapeutic strategies.