Origin of the Anomalous Guest Polymer Selectivity in Complex Coacervates

Abstract Complex coacervates─liquid condensates resulting from liquid–liquid phase separation of oppositely charged polymers─have attracted broad interest in artificial cells, drug delivery vehicles, and smart nanoreactors. The functionality of these applications is significantly influenced by the coacervate’s ability to encapsulate guest macromolecules, where the guest interactions determine their loading efficiency and activity. Using MD simulations, analytical theory, and experiments, we demonstrate that the intrinsic electrostatic correlations within the coacervate matrix significantly modify the effective interactions of guest polymers in the dense phase, resulting in the strong dependence of encapsulation on guest chain length, charge density, and charge sequence observed experimentally. Even in the absence of chemical incompatibility, neutral polymers are strongly excluded from the coacervate phase as a result of disrupting electrostatic correlations within coacervates. Consequently, the encapsulation efficiency of neutral polymers exponentially decays with increasing guest chain length. For polyampholyte-like intrinsically disordered proteins (IDPs), their effective interaction within coacervates is largely determined by charge sequence: IDPs with more-disordered sequences experience strict rejection from the dense phase, whereas those with more blocky charges are dispersed within coacervates. Interestingly, for all the guest species tested, their effective interactions are opposite to those observed in dilute solutions, where the sign of the effective two-body interaction reverses when going from the dilute phase to the dense coacervate phase. We elucidate that the non-trivial guest selectivity in complex coacervates originates from the disruption of polycation–polyanion electrostatic correlations by the guest, which combines an energetic penalty (dilution of charge density) with an entropic penalty (loss of chain conformational freedom of the host). These findings have significant implications for understanding guest behavior in coacervate and biocondensate systems.