Host cell membrane

The host cell membrane and internal endosomal membranes function as the critical interface and primary biological barrier for the delivery of lipid nanoparticle (LNP) therapeutics. LNPs typically gain entry into the cell through receptor-mediated endocytosis, a process often facilitated by the adsorption of endogenous Apolipoprotein E (ApoE) which targets the Low-Density Lipoprotein Receptor (LDLR) on the cell surface (PubMed: 23242218). Following internalization, the LNP is sequestered within an endocytic vesicle where the decreasing pH triggers the protonation of ionizable lipids, leading to a structural transition that disrupts the endosomal membrane (Nature Nanotechnology: 10.1038/nnano.2012.232). This process, known as endosomal escape, is the essential step for releasing nucleic acid cargo, such as mRNA or siRNA, into the cytoplasm where it can exert its biological effect (Chemical Reviews: 10.1021/acs.chemrev.1c00244). Despite its importance, endosomal escape is highly inefficient, with only a small fraction of the internalized dose typically reaching the cytosol (Nature Biotechnology: 10.1038/nbt.3298). Consequently, the host cell membrane's composition and the LNP's ability to interact with it are central focuses in the development of vaccines and gene therapies for cancer, infectious diseases, and genetic disorders (Advanced Drug Delivery Reviews: 10.1016/j.addr.2021.05.016).

Other names

Plasma membraneEndosomal membraneCellular lipid bilayerEndocytic vesicle membraneCytoplasmic membrane

Lipid nanoparticles (LNPs) interact with the host cell membrane to trigger receptor-mediated endocytosis and subsequently utilize the acidic environment of the endosome to induce membrane disruption, facilitating the escape of nucleic acid cargo into the cytosol.