Cellular membranes and associated uptake machinery (LNP uptake machinery)

Cellular membranes and associated uptake machinery represent the biological interface through which lipid nanoparticles (LNPs) deliver therapeutic payloads, such as mRNA or siRNA, into target cells. This system involves the plasma membrane, various surface receptors—most notably the low-density lipoprotein receptor (LDLR)—and the complex endocytic pathway. LNPs often exploit endogenous proteins like Apolipoprotein E (ApoE) to facilitate receptor-mediated endocytosis, a process critical for efficient cellular entry in the liver and other tissues (Cullis and Hope, 2017, Molecular Therapy). Once inside the cell, the machinery includes the endosomal system, where the LNP must undergo endosomal escape to avoid lysosomal degradation. This escape is typically driven by the interaction between pH-responsive ionizable lipids in the LNP and the anionic lipids of the endosomal membrane. This interaction is the primary bottleneck for LNP-mediated drug delivery, as only a small fraction of the cargo typically reaches the cytosol. Consequently, this machinery is a major focus for optimizing the efficacy and safety of genetic medicines and vaccines.

Other names

Endocytic pathwayLNP delivery interfacePlasma membrane uptake systemEndosomal escape pathwayApoE-LDLR uptake axis

Lipid nanoparticles (LNPs) utilize endogenous pathways for cellular entry, primarily through the adsorption of Apolipoprotein E (ApoE) which mediates binding to the Low-density lipoprotein receptor (LDLR) on the cell surface (Akinc et al., 2010, Nature Biotechnology). This triggers clathrin-mediated endocytosis or macropinocytosis. Once internalized, the acidic environment of the endosome protonates the ionizable lipids within the LNP, causing membrane fusion or disruption (endosomal escape) and subsequent release of the nucleic acid cargo into the cytoplasm (Sahay et al., 2013, Nature Nanotechnology).