Decoding the tactics for coacervate pedestrian crossing the phospholipid membrane

Coacervate microdroplets based on liquid-liquid phase separation (LLPS) have emerged as versatile models for protocells, membraneless organelles and smart drug delivery carriers. Understanding the mechanisms of coacervates crossing lipid membranes is of great significance in synthetic cell engineering, cell physiology analysis, and transmembrane drug delivery. In this review, we systematically summarize the mechanisms by which coacervates cross phospholipid bilayers of liposomes or cells, which are classified based on whether membrane-remodelling processes are present. Two major mechanisms are introduced, including vesicular engulfment driven by electrostatic interaction, photoswitchable phospholipids, caveolin and actin polymerization, and direct penetration mediated by lipid rafts and phospholipid defects. These findings deepen the understanding of mass and signal exchange across cellular boundaries and underscore the potential applications of coacervates for sophisticated synthetic cells, biosensors and drug delivery systems.