FIGURE 1.

Schematic diagram of major interactions in the model for antisense delivery and activity. AS ONs (shown in red throughout) in the extracellular environment (A_b) bind to cellular surface molecules (R) and are internalized by endocytosis. The oligonucleotides that are internalized (A_i) must escape the endosome to enter the cytoplasm (A_c) before routing and degradation in lysosomes (X). Once in the cytoplasm, AS ONs can find their complementary target mRNA (M) and hybridize to form a duplex (D). The duplex is incapable of translation, and the mRNA portion may be degraded by Rnase H. Hybridization of cytoplasmic oligonucleotides to nontarget mRNA (N) is also possible, and these duplexes would also serve as substrates for Rnase H. Definition of all variables can be found in the main text.