Water‐Soluble Lipophilic Near‐Infrared Region II Fluorophores for High‐Brightness Lipid Layer and Lipid Droplets Imaging Applications

Fluorescence imaging in the second near-infrared region (NIR-II, 1000-1700 nm) has garnered considerable attention for displaying the biological information of deep tissues. However, the lack of biocompatible contrast agents with bright NIR-II emission has hampered the precise clinical application of deep tissue imaging. Here, a lipophilic enhancement strategy employing donor-acceptor-donor (D-A-D) molecules, introducing long alkoxy chains and quaternary ammonium salts for the development of highly bright water-soluble NIR-II fluorophores (BBTD-2C-N), is described. Notably, liposome-encapsulated BBTD-2C-N nanoparticles (B-2C-N/DMPC) in aqueous solution exhibit a 1.8-fold increase in NIR-II fluorescence brightness compared to free BBTD-2C-N in methanol. Avoidance of the aggregation-caused quenching effect and enhanced NIR-II fluorescence are attributed to significantly attenuated π-π stacking interactions and maintained monodisperses in the hydrophobic liposome shell. Moreover, BBTD-2C-N demonstrates superior performance in visualizing lipid droplet-rich HeLa cells in vitro, as well as precise monitoring of adipose tissue and fatty liver in vivo. This study reveals a new avenue for the development of bright NIR-II fluorophores and precise in vivo imaging.