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. 2021 Feb 16;296:100416. doi: 10.1016/j.jbc.2021.100416

Figure 6.

Figure 6

Mechanisms of PS ASO cellular uptake and release.A, cell surface PS ASO adsorption. Different cell surface proteins, including receptors, can interact with PS ASOs either directly or via ligands conjugated to PS ASOs. Cell surface proteins can direct the internationalization of PS ASOs through clathrin- or caveolin-dependent endocytic pathways or via nonconventional endocytic pathways. B, PS ASOs can enter cells via different endocytic pathways including macropinocytosis. The macropinocytosis pathway may represent a nonproductive pathway for unformulated ASOs. PS ASO internalization via nonconventional endocytic pathways is only conjecture. Internalized PS ASOs normally traffic from early endosomes (EE) to late endosomes (LE) and to lysosomes. PS ASOs must escape from endocytic organelles to be effective. LEs appear to be the major productive release site. Several release pathways may exist, including back-fusion-mediated, membrane leakage, and vesicle-mediated PS ASO release. Released PS ASOs can interact with cellular proteins and enter nucleus.