Endosomal escape pathway

The endosomal escape pathway is a critical biological process by which internalized molecules, such as therapeutic nucleic acids or proteins, exit endocytic vesicles (endosomes) into the cytosol before they are degraded in lysosomes (Smith et al., 2019). This process is a major bottleneck in the delivery of advanced therapeutics, including mRNA vaccines and siRNA-based drugs, which require access to the cytoplasm or nucleus to exert their effects (Varkouhi et al., 2011). Various strategies are employed to facilitate escape, such as the "proton sponge" effect, where buffering of the endosome leads to osmotic swelling and rupture, or the use of fusogenic lipids that merge with the endosomal membrane (Cullis & Hope, 2017). Efficient endosomal escape is essential for the pharmacological activity of drugs like Patisiran or mRNA-based COVID-19 vaccines, as failure to escape results in sequestration and subsequent enzymatic degradation within the late endosome or lysosome (Wittrup et al., 2015). Understanding and optimizing this pathway is a central focus in the development of non-viral delivery systems, as it directly impacts the potency and safety of gene and RNA therapies.

Other names

Endosomal escapeEndosomal releaseCytosolic deliveryEndosomal escape mechanism

Facilitation of cargo release from endosomes into the cytoplasm via mechanisms such as the proton sponge effect, membrane fusion, or membrane destabilization induced by delivery vehicles.