Electron density engineering of chalcone derivatives towards synergistically strengthened lipid droplet probes for fluorescence diagnosis and drug evaluation of non-alcoholic fatty liver disease.

Detecting abnormal lipid levels and timely intervention have great potential for diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD). Herein, a novel molecular electron density engineering strategy for synergistically strengthened lipid droplets (LDs) fluorescence probes based on the chalcone skeleton is presented for simultaneous fluorescence diagnosis and drug evaluation of NAFLD. Specifically, a series of novel chalcone derivatives (C1-C7) with controlled intrinsic electron density distribution are rationally fabricated via introducing various push-pull electronic groups into triphenylamine-fused chalcones. Notably, the optical properties including polarity sensibility, Stokes shift, fluorescence emission, photostability, and aggregation-induced emission (AIE) characteristics are all synergistically boosted upon transforming from D-π-A-π-D to D-π-A-π-A architectures. C2 is identified as the optimal probe for LDs-targeted dynamic high-fidelity fluorescence monitoring in live cells, revealing a novel LDs motion pattern termed "Sequential Separation". Further, C2 permits multiscale fluorescence imaging diagnosis of NAFLD in vitro/vivo. Moreover, two LDs-based drug evaluation protocols utilizing C2 for NAFLD intervention are first established, and sesamol is identified as a potential NAFLD therapeutic agent through these assays. Overall, this work not only provides a rational design strategy and novel probe toolbox for the early diagnosis of NAFLD, but also develops pioneering drug screening methodologies for exploiting potential NAFLD therapeutic drugs.