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

Abstract

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.