A Molecular View of the Osmotic Response of Polyelectrolyte Complex Coacervates

Synthetic polyelectrolyte complex coacervates are a ubiquitous class of liquid–liquid phase-separated (LLPS) systems that closely mimic the dynamic condensates often seen in cellular environments, where macromolecular crowding fundamentally shapes their physicochemical properties and biological function. For synthetic systems, neutral crowding agents, such as poly(ethylene glycol) (PEG), enhance coacervation, although the direct impact of osmotic stress on the structural and thermodynamic stability of the dense coacervate phase remains incompletely understood. Here, we utilize coarse-grained molecular simulations alongside systematic experimental studies to reveal the intrinsic compressibility and hydration dynamics of the coacervate phase under controlled osmotic perturbations. This framework establishes quantitative design principles for engineering synthetic condensates with programmable mechanical stability in macro-molecular crowded environments, with direct implications for developing biomimetic organelles that maintain structural integrity within the crowded cellular environment.