Endogenous H2S-Activated Orthogonal Second Near-Infrared Emissive Nanoprobe for In Situ Ratiometric Fluorescence Imaging of Metformin-Induced Liver Injury

Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H₂S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H₂S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H₂S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF₄:Gd/Yb/Er@NaYF₄:Yb@SiO₂ coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF₄:Gd/Yb/Er@NaYF₄:Yb@SiO₂@Ag₂S via in situ sulfuration reaction triggered by the overexpressed endogenous H₂S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H₂S. More importantly, the in situ highly specific ratiometric imaging of the metformin-induced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.