Figure 6. RNA delivery to the cytosol.
The prevailing hypothesis is that the hexagonal lipid phase in nanoparticles within endosomes catalyzes lipid exchange that destabilizes the composition of the anionic endosomal membrane.78 The suggested flow of events is that lipid nanoparticle (LNP) entry into endosomes is followed by electrostatic interaction of cationic, ionizable lipids in the LNP with the anionic lipids in the endosomal membrane. This interaction leads to lipid exchange and fusion of the particle with the endosomal lipid phase, followed by nucleic acid escape to the cytoplasm, possibly assisted by the endosomal proton pump, which is activated by cationic lipids. Every proton leads to the importation of a chloride and water molecule, leading to increased hydrostatic pressure. Reprinted with permission from ref 78 under the terms of the Creative Commons Attribution 3.0 License. Copyright 2012 The Authors.