Anionic endosomal membrane lipids

Anionic endosomal membrane lipids, primarily bis(monoacylglycero)phosphate (BMP) and phosphatidylinositol 3-phosphate (PI3P), are specialized phospholipids that define the identity and function of endocytic compartments (Gruenberg, J., Nature Reviews Molecular Cell Biology, 2020). These lipids are essential for regulating membrane protein sorting, vesicle formation, and the internal architecture of late endosomes. In the context of modern pharmacology, they serve as the primary target for ionizable lipid-based delivery systems, such as lipid nanoparticles (LNPs) used in mRNA vaccines and siRNA therapeutics (Cullis, P. R., & Hope, M. J., Molecular Therapy, 2017). When LNPs enter the acidic environment of the endosome, their ionizable lipids become protonated and bind to these anionic lipids, triggering a transition from a stable bilayer to a destabilizing hexagonal phase (Sahay, G., et al., Nature Biotechnology, 2013). This structural change is the fundamental mechanism of endosomal escape, allowing nucleic acids to reach the cytosol. Furthermore, these lipids are exploited by various viruses for membrane fusion and are implicated in the pathology of lysosomal storage diseases, such as Niemann-Pick disease, where their metabolism is significantly disrupted (Kolter, T., & Sandhoff, K., Annual Review of Cell and Developmental Biology, 2005).

Other names

Endosomal anionic lipidsNegatively charged endosomal lipidsBis(monoacylglycero)phosphateBMPLysobisphosphatidic acidLBPAPhosphatidylinositol 3-phosphatePI3PPhosphatidic acidEndosomal phospholipids

Ionizable lipids in delivery vehicles undergo protonation in the acidic endosomal environment, leading to electrostatic interaction with anionic endosomal membrane lipids. This interaction induces a transition from a lamellar to an inverted hexagonal (HII) phase, destabilizing the endosomal membrane and facilitating the cytosolic release of therapeutic cargo (Cullis, P. R., & Hope, M. J., Molecular Therapy, 2017; Sahay, G., et al., Nature Biotechnology, 2013).