Sticker-Spacer Molecular Design Controls Coacervate Formation and Internal Microenvironments in Low-Molecular-Weight Compounds

Coacervates formed via liquid-liquid phase separation have been established as potential protocells in life studies. Unlike widely studied macromolecules, coacervates from low-molecular-weight (<i>M</i> _w) 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-<i>M</i> _w compounds containing two aromatic or cycloalkane stickers linked via a flexible hydrophilic spacer. These low-<i>M</i> _w compounds self-assemble into micrometer-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. Importantly, subtle variations in the chemical structures of the sticker groups resulted in significant differences in the internal microenvironments of the coacervates. Delicately balanced coacervates facilitate the interfacial accumulation of polysaccharides bearing appropriate fluorescent dyes, which effectively stabilize the coacervates against size expansion due to coalescence. This research highlighting a rational molecular design for the construction of modulable simple coacervates composed of low-<i>M</i> _w compounds offers an opportunity to explore bioapplications as biofunctional soft materials and construct more complicated coacervate-based protocell models.