Lipid droplet-targeted near-infrared fluorescent probes for polarity detection and identification of non-alcoholic fatty liver disease

Abstract

As the core organelle responsible for the storage and metabolism of intracellular neutral lipids, lipid droplets (LDs) undergo dynamic changes in the polarity of their microenvironment. These changes not only serve as important indicators of the cellular lipid metabolism state but are also closely associated with the pathological processes of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD). Most of the existing fluorescent probes have weak targeting ability or limited sensitivity to polarity, making it difficult to meet the requirements for dynamic monitoring at the level of living cells and organisms. This severely restricts in-depth analysis of the pathological process of NAFLD and early diagnosis. Based on this, in this study, four LD-targeted fluorescent probes (LS1–LS4) with D–π–A configurations were designed and synthesized using phenothiazine as the core and by introducing different terminal groups. The aim is to achieve highly sensitive and specific detection of the polarity changes in the LD microenvironment. Through optical research, it was observed that probes LS1–LS4 exhibited red light emission in low-polarity solvents and could emit in the near-infrared region in highly polar solvents, and all probes were highly sensitive to polarity. In biological experiments, probe LS3 demonstrated a washing-free effect on cells and rapid cellular uptake. Notably, LS3 was capable of reflecting intracellular polarity changes included by drug stimulation through alterations in LD characteristics, such as fluorescence intensity, quantity, and size. More importantly, in the mouse model of non-alcoholic fatty liver, probe LS3 can distinguish normal organs from NAFLD organs. In summary, this study provides novel tools for monitoring NAFLD and suggests that polarity changes may contribute to the development of treatments for associated diseases.