Membrane fusion-based drug delivery liposomes transiently modify the material properties of synthetic and biological membranes

Abstract Many drug targets are located in intracellular compartments of cells but they often remain inaccessible to standard imaging and therapeutic agents. To aid intracellular delivery, drug carrier nanoparticles have been used to overcome the barrier imposed by the plasma membrane. The carrier must entrap large amounts of cargo, efficiently and quickly deliver the cargo in the cytosol or other intracellular compartments, and must be as inert as possible. In other words, they should not induce cellular responses or alter the cell state in the course of delivery. Here, we show that cationic liposomes with high charge density efficiently fuse with synthetic membranes and the plasma membrane of living cells. Direct fusion efficiently delivers large amounts of cargo to cells and cell-like vesicles within seconds, bypassing slow and often inefficient internalization-based pathways. These effects depend on liposome charge density and, to some extent, liposome concentration and the helper lipid. However, fusion-mediated cargo delivery results in the incorporation of large amounts of foreign lipids that leads to changes in the material properties of these membranes, namely modifications in membrane packing and fluidity, induction of membrane curvature, decrease in surface tension and the formation of (short-lived) pores. Importantly, these effects are transient and liposome removal allows cells to recover their state prior to liposome interaction.