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

Abstract

Abstract 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.