Negatively charged cellular and endosomal membranes

Negatively charged cellular and endosomal membranes serve as critical interfaces for therapeutic intervention, particularly in oncology, infectious disease, and advanced drug delivery (Birge et al., 2016, Cell Death & Differentiation). These membranes are characterized by an abundance of anionic phospholipids, such as phosphatidylserine (PS) in apoptotic or malignant cells, and phosphatidylglycerol or lipopolysaccharides in bacterial cells (Epand et al., 2016, Biochimica et Biophysica Acta). In healthy mammalian cells, these lipids are typically sequestered in the inner leaflet of the plasma membrane, but their exposure on the outer surface in pathological states provides a selective docking site for cationic antimicrobial peptides and targeted antibodies. Furthermore, the acidic and negatively charged environment of the endosomal membrane is exploited by ionizable lipid nanoparticles (LNPs) to facilitate endosomal escape, a key step in the delivery of nucleic acid therapeutics like mRNA vaccines (Sahay et al., 2013, Nature Biotechnology). By leveraging electrostatic interactions, drugs can achieve selective binding and subsequent membrane disruption or cargo release. However, therapeutic challenges include potential off-target toxicity to healthy anionic structures, such as mitochondrial membranes, and the risk of systemic hemolysis.

Other names

Anionic lipid membranesAnionic phospholipidsNegatively charged lipid bilayersPhosphatidylserine-exposed membranesAnionic cell surfaces

Electrostatic interaction between cationic drug components and anionic lipids leading to membrane permeabilization, pore formation, or pH-dependent endosomal escape via the proton sponge effect.