Kinetically Controlled Self‐Assembly of a Lipophilic Fluorophore with Phenylalanine‐Based Diamides in Artificial Lipid Droplets

ABSTRACT Lipid droplets (LDs) are vital organelles that govern energy storage and lipid metabolism in cells. The ability to direct the self‐assembly of small molecules into defined nanostructures within LDs would provide opportunities to modulate their functions. Although supramolecular polymerization has been extensively investigated in low‐polarity media, achieving controlled molecular assembly in neutral lipid droplets remains a formidable challenge. Here, we report the design of a lipophilic donor–acceptor‐type fluorophore bearing phenylalanine‐derived diamide units, which undergoes controlled supramolecular polymerization in the neutral lipid triolein. In triolein, the molecule assembles into fibrous aggregates that display intense fluorescence and a pronounced Cotton effect in circular dichroism spectrum. Spectroscopic and microscopic analyses reveal that a seeding strategy accelerates the conversion from a kinetically trapped monomeric state to fibrous assemblies. Furthermore, fluorescence imaging in artificial LDs demonstrates that aggregate size can be tuned through the seeding process.