Ketocyanine‐Based Fluorescent Probe Revealing the Polarity Heterogeneity of Lipid Droplets and Enabling Accurate Diagnosis of Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC) has gradually become a pronoun for terrifying death owing to its high mortality rate. With the progression of HCC, lipid droplets (LDs) in HCC cells exhibit specific variations such as increased LDs number and decreased polarity, which can serve as the diagnostic target. However, developing an effective method to achieve HCC diagnosis and reveal LDs polarity heterogeneity is still a crucial challenge. Herein, the first high‐performance LDs‐targeting probe ( 1 ) is reported based on ketocyanine strategy with ultrasensitive polarity‐responding ability and near‐infrared emission. Probe 1 shows excellent sensitivity to polarity parameter Δ f (0.027–0.290) with 808‐fold fluorescence enhancement and the emission wavelength red‐shifts 91 nm. In HCC cells, probe 1 shows a 2.5‐ to 5.9‐fold fluorescence enhancement compared with normal and other cancer cells which exceeds clinical threshold of 2.0, indicating probe 1 can distinguish HCC cells. The LDs polarity heterogeneity is revealed and it displays a sequence, HCC cells < other cancer cells < normal cells, which may provide useful insight to engineer LDs‐targeting probes for HCC cell discrimination. Finally, probe 1 realizes accurate HCC diagnosis on the cellular, organ, and in vivo levels, providing a satisfying tool for clinical HCC diagnosis and surgical navigation.