Lysosome-Assisted Mitochondrial Targeting Nanoprobe Based on Dye-Modified Upconversion Nanophosphors for Ratiometric Imaging of Mitochondrial Hydrogen Sulfide

Hydrogen sulfide (H2S) is a versatile modulator in mitochondria and involved in numerous diseases caused by mitochondrial dysfunction. Therefore, many efforts have been made to develop fluorescent probes for mitochondrial H2S detection. However, these cationic small molecule probes are inapplicable for in vivo imaging because of the shallow tissue penetration and poor biostability. Herein, a ratiometric upconversion luminescence nanoprobe with an acid-activated targeting strategy is developed for detecting and bioimaging of mitochondrial H2S. The merocyanine triphenylamine-merocyanine (TPAMC)-modified upconversion nanophosphors, acting as the targeting and response component, are encapsulated into a pH-sensitive husk, composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(poly(ethylene glycol))-2000] (DSPE-PEG) and poly(l-histidine)-b-PEG, which improved the nanoprobe’s stability during transport in vivo. Under lysosomal pH, the PEG shell is interrupted and the targeting sites are exposed to further attach to mitochondria. Taking advantage of the luminescence resonance energy transfer process between TPAMC and upconversion nanophosphors, the ratiometric detection of mitochondrial H2S can be achieved with high selectivity and sensitivity. Cellular testing reveals the precise targeting to mitochondria via a lysosome delivery process. Importantly, the nanoprobe can be used for monitoring mitochondrial H2S levels in living cells and colon cancer mouse models.