Figure 1.

Examples of delivery agents and of their modes of action. A) The acidic pH of the late endosome protonates the amphiphilic peptide HA2, triggering a conformational change that promotes membrane insertion and membrane permeabilization. B) In the presence of light, photosensitizers generate reactive oxygen species (ROS) that oxidize membranes, leading to membrane permeabilization. C) Lipoplex- and LNP-mediated escape is triggered by electrostatic interactions between the cationic lipids of the lipoplex and the anionic phospholipids present in endosomes. In addition, lipid mixing with fusogenic cellular lipids enable the cytosolic penetration of nucleic acid cargo. D) Electrostatic interactions between the arginine-rich CPP dfTAT and anionic intraluminal vesicles trigger bilayer contact among late endosomal membranes. This, in turn, promotes leaky fusion and cytosolic release. For all examples, the endosomal escape events are shown as taking place in late endosomes. These organelles are not necessarily the only site of escape for these reagents (e.g. HA2, photosensitizers). Yet, the presence of BMP, a lipid that is both anionic and fusogenic, makes the membranes of late endosomes, and not the PC-enriched plasma membrane, likely targets of cationic delivery reagents.