Cholesterol-Rich Membranes Wetting by Polypeptide Coacervate: Pathway and Mechanism via the Liquid-Disordered Phase

Polypeptide coacervates exhibit remarkable cell membrane permeability for drug delivery, but the precise internalization mechanism is unclear. Here, taking histidine-rich beak derivative protein (HBpep-SR) coacervate as a model, we investigate the interactions of coacervates with ternary lipid raft membranes and mammalian plasma membranes using the Martini 3.0 force field. We show that coacervates preferentially wet the liquid disordered (Ld) phase in a cholesterol-dependent manner with an encapsulation efficiency in the Ld phase of approximately 60%. In rigid, cholesterol-depleted ternary membranes, coacervates fail to induce membrane bending and disperse over time. Conversely, the flexibility of unsaturated lipids in the Ld phase of lipid rafts promotes coacervate wrapping, a process mediated by aromatic rings in polypeptides. Similar trends are observed in plasma membrane systems and other polypeptide coacervate systems. Our findings reveal a universal pathway for coacervate uptake via Ld regions, offering crucial insights for designing coacervates with enhanced cellular internalization.