Targeted inhibition of gene expression can be achieved by:
Antisense oligonucleotides synthetic single-stranded nucleic acids 16-20 nucleotides bearing phosphorothioate backbone replacing nonbridging oxygen sulfur increasing nuclease resistance albumin binding prolonging half-life, 2 prime O-methoxyethyl sugar increasing affinity Tm 2 degrees per modification reducing immune stimulation TLR7/8, locked nucleic acids constraining ribose C3 endo enhancing hybridization strength. Binding target mRNA via Watson-Crick pairing forming heteroduplex nucleus or cytoplasm, two mechanisms dominate: recruitment endogenous RNase H1 hydrolyzing RNA strand DNA-RNA hy
Ref: FDA Antisense Oligonucleotide Guidance 2023; Nature Reviews Drug Discovery Antisense Mechanism 2021; Alberts Molecular Biology RNA Targeting Chap 8.