Oligopeptides/DNA Coacervate Droplets as Macromolecular Delivery Microcarriers

ABSTRACT Macromolecular therapeutics demonstrate significant advantages and potential for treating diverse diseases. However, their intrinsic physicochemical properties often hinder the selection of suitable carriers for efficient intracellular delivery. Here, we develop coacervates formed via liquid–liquid phase separation of oligopeptides and DNA as macromolecular carriers for cellular membrane translocation. These materials enable the efficient recruitment and release of biomacromolecules, including proteins and enzymes. Notably, our experimental data suggest that their uptake may not be entirely identical to classical endocytic pathways and instead involves cholesterol‐dependent lipid raft interactions, indicating a mechanism that may be distinct from canonical clathrin‐mediated endocytosis. Upon reaching the cytoplasm, the DNA component of the coacervates is degraded by intracellular DNA‐processing enzymes, leading to coacervate disassembly and subsequent release of the therapeutic macromolecules. Together, these coacervates establish a generalizable platform for intracellular delivery of macromolecular therapeutics, integrating membrane translocation with programmable cytosolic release.