Minimalist Molecules Drive Liquid–Liquid Phase Separation to Modularly Assemble Functional Coacervate Protocells

Although coacervates formed via liquid-liquid phase separation (LLPS) are widely considered plausible protocell models relevant to the origin of life, identifying minimalist, ultralow-molecular-weight molecules (M_w <300 Da) capable of undergoing LLPS remains a major challenge. Here we present a class of synthetic phase-separating molecules with M_w ranging from 211 to 215 Da-among the smallest known to drive coacervation. These molecules feature a modular design comprising a hydrophobic head and a hydrophilic tail, forming a minimalistic framework that significantly reduces molecular freedom and enables precise dissection of the fundamental interactions governing LLPS. Our findings reveal that LLPS is governed by a delicate balance between intermolecular non-covalent interactions and molecular solvation. Furthermore, this molecular architecture serves as a versatile synthon for modularly constructing a range of task-specific coacervates, including proton-responsive, redox-responsive, light-responsive, and self-fluorescent variants. These coacervates selectively accumulate diverse guest molecules and act as efficient bio-crucibles that support key prebiotic processes, such as amino acid-involved C─N coupling reactions, chiral catalysis, DNA hybridization, and energy transfer. These results provide both a molecular framework and chemical insights into the minimal requirements for LLPS, while advancing the coacervate toolkit for origins-of-life studies and synthetic cell engineering.