Neutral lipids may act as functional medium for controlling supramolecular polymerization

The formation of supramolecular polymers within living cells is an emerging strategy for regulating cellular functions, and lipid droplets (LDs) are promising environments for such processes. LDs are cellular organelles composed mainly of neutral lipids, such as triacylglycerols and cholesterol esters, and are deeply involved in cellular functions. However, the self-assembly of supramolecular polymers in neutral lipid-rich environments, such as LDs, is not well understood. To this end, researchers from WPI-ITbM at Nagoya University in Japan have achieved programmable construction of supramolecular polymers in triolein (TO), one of the most abundant lipid components of LDs. This research was published in Nature Communications on July 6, 2026.

While conventional polymers are held together by covalent bonds, supramolecular polymers are held together by non-covalent interactions (e.g. hydrogen bonds and stacking). They are more life-like, capable of assembling, disassembling, and reorganizing. For their studies, they analyzed green and blue fluorescing monomers and their supramolecular polymerization in TO, a biologically relevant triacylglycerol, to mimic the conditions found in LDs. For comparison, they also analyzed polymerization in dibutyl ether (DBE), which has a similar polarity. Notably, the neutral-lipid medium of TO provided excellent conditions for precision-controlled supramolecular polymer growth.

By using fluorescent monomers, they could effectively track the polymerization process, such as initial nucleation steps and aggregation, using fluorescence imaging techniques. Ultrasonicating monomer 1 in TO promoted aggregation and green-emitting aggregates could be obtained.

Significant differences were observed in the process leading up to aggregation in TO and DBE. While monomer 1 immediately began to aggregate in DBE, a distinct lag was observed before the onset of aggregation in TO (~35 minutes). While both TO and DBE have similar polarity, TO's structure temporarily stabilizes the monomers and suppresses spontaneous nucleation through transient hydrogen bonding interactions. Furthermore, the environment of the TO medium also suppressed undesirable aggregation between formed supramolecular polymer fibers. These fibers remained dispersed in TO, whereas they quickly aggregated together in DBE.

These attributes of TO provided the ideal conditions to grow supramolecular polymers in a controlled manner and demonstrated this by growing polymers made up of alternating green and blue emitting monomers 1 and 2. By using a supramolecular polymer of green-emitting monomer 1 as a seed and subsequently adding blue-emitting monomer 2, they successfully formed a triblock supramolecular polymer with a green-emitting center and blue-emitting termini. Furthermore, they formed pentablock supramolecular polymers by adding the green emitting monomer 1 to the triblock supramolecular polymer. These structures were directly visualized using confocal laser microscopy.

These results suggest that the neutral lipids found in LDs may act as a functional medium for controlling supramolecular polymerization. This study provides design guidelines for self-assembling molecules operating in a neutral lipid environment, as well as fundamental insights for the development of molecular technologies targeting intracellular lipid environments. In the future, this research is expected to contribute to the development of treatments for diseases involving LDs and to the elucidation of organelle functions.