Impact of molecular structure as sticker–spacer model on formation and internal environments of coacervates composed of low-molecular- weight compounds

Coacervates formed through liquid–liquid phase separation have been established as potential protocells. Unlike widely studied macromolecules, coacervates from low-molecular-weight compounds have recently gained importance because they provide simple but valuable in vitro models for biomolecular condensates and serve as promising platforms for the development of functional biomaterials. Herein, we present a modular molecular design for the phase separation of low-molecular-weight compounds containing two aromatic or cycloalkane stickers linked via a flexible hydrophilic spacer. These low-molecular-weight compounds self-assemble into micron-scale liquid-like coacervates at submillimolar concentrations. The coacervates provide a hydrophobic internal microenvironment that can selectively sequester hydrophobic guest molecules while excluding hydrophilic molecules. We demonstrate the controlled release of hydrophobic drugs encapsulated in reduction-responsive coacervates composed of nitrophenyl groups as stickers that are cleaved by the addition of a reductant to induce the disassembly of the coacervates. This research is based on a rational molecular design for the construction of simple coacervates composed of low-molecular-weight compounds and offers an opportunity to construct more complicated coacervate-based protocell models and biofunctional soft materials.