A near-infrared phenothiazine-derived lipid droplet-targeted fluorescent probe for polarity sensing and its application in liver disease diagnosis

Non-alcoholic fatty liver disease (NAFLD) and acute alcoholic liver injury (AALI) are prevalent hepatic disorders and their asymptomatic early stages pose significant challenges for clinical diagnosis. Abnormal changes in lipid droplets (LDs) polarity are closely related to various cellular activities and disease progression and are considered a highly promising early biomarker for liver disease. Therefore, the accurate detection of LDs polarity is crucial for the early warning and intervention of liver disease. Against this background, two polarity-sensitive fluorescent probes HC1 and HC2 were developed, using phenothiazine as the core scaffold. Both probes featured a large Stokes shift (>210 nm), emission in the near-infrared region (>650 nm) and a specific response to polarity. Notably, HC2 exhibited excellent linear correlations with the polarity parameter (Δf), as reflected in both its fluorescence intensity and its maximum emission wavelength. Biological experiments demonstrated that HC2 could rapidly target LDs within 10 s in live cells and enabled monitoring of changes in LDs polarity, number and size under stimulation with various drugs, including metformin (Met) and sorafenib. Importantly, HC2 allows precise imaging of mice tissues and organs affected by NAFLD and AALI. Collectively, probe HC2 is a promising candidate not only for the early diagnosis of liver diseases but also for studying polarity-related pathological processes.