RNA therapeutics involve oligonucleotides that bind RNA through base pairing to modulate gene expression. Three main technologies are RNA interference (RNAi), antisense oligonucleotides (ASOs), and steric-blocking oligonucleotides. RNAi and ASOs reduce gene expression by degrading mRNA, while steric-blocking oligonucleotides prevent access to RNA without degrading it, allowing alternative splicing, RNA repair, and protein restoration. These latter can be chemically modified for better drug-like properties. Clinical trials for Duchenne muscular dystrophy (DMD) show promise for steric-blocking oligonucleotides. RNAi and ASOs target mRNA for gene silencing, but their use is limited by poor intracellular uptake and the need for limited chemical modifications. Steric-blocking oligonucleotides, which block RNA without degradation, are more flexible and can be extensively modified. They are effective in diseases like DMD, where they can restore dystrophin function by skipping defective exons. PMO and 2'-OMe PS SSOs have shown success in DMD, with some trials showing significant dystrophin restoration. Steric-blocking oligonucleotides also treat other diseases, such as spinal muscular atrophy (SMA) and β-thalassemia, by modulating splicing. In SMA, SSOs target SMN2 pre-mRNA to restore SMN protein. In β-thalassemia, SSOs correct splicing defects in β-globin pre-mRNA. These therapies have shown promise in preclinical models and some clinical trials. SSOs can also modulate alternative splicing of non-defective genes, offering broad therapeutic applications. For example, in inflammatory diseases, SSOs can generate soluble decoy receptors that inhibit pro-inflammatory cytokines. In myotonic dystrophy, SSOs target CUG repeats to restore splicing and prevent disease progression. Additionally, steric-blocking oligonucleotides can be used for antibacterial and antiviral therapies by down-regulating undesirable proteins. PMOs have shown effectiveness in inhibiting bacterial growth and gene expression in E. coli and B. subtilis. These findings highlight the versatility of RNA-based therapeutics in treating a wide range of diseases.RNA therapeutics involve oligonucleotides that bind RNA through base pairing to modulate gene expression. Three main technologies are RNA interference (RNAi), antisense oligonucleotides (ASOs), and steric-blocking oligonucleotides. RNAi and ASOs reduce gene expression by degrading mRNA, while steric-blocking oligonucleotides prevent access to RNA without degrading it, allowing alternative splicing, RNA repair, and protein restoration. These latter can be chemically modified for better drug-like properties. Clinical trials for Duchenne muscular dystrophy (DMD) show promise for steric-blocking oligonucleotides. RNAi and ASOs target mRNA for gene silencing, but their use is limited by poor intracellular uptake and the need for limited chemical modifications. Steric-blocking oligonucleotides, which block RNA without degradation, are more flexible and can be extensively modified. They are effective in diseases like DMD, where they can restore dystrophin function by skipping defective exons. PMO and 2'-OMe PS SSOs have shown success in DMD, with some trials showing significant dystrophin restoration. Steric-blocking oligonucleotides also treat other diseases, such as spinal muscular atrophy (SMA) and β-thalassemia, by modulating splicing. In SMA, SSOs target SMN2 pre-mRNA to restore SMN protein. In β-thalassemia, SSOs correct splicing defects in β-globin pre-mRNA. These therapies have shown promise in preclinical models and some clinical trials. SSOs can also modulate alternative splicing of non-defective genes, offering broad therapeutic applications. For example, in inflammatory diseases, SSOs can generate soluble decoy receptors that inhibit pro-inflammatory cytokines. In myotonic dystrophy, SSOs target CUG repeats to restore splicing and prevent disease progression. Additionally, steric-blocking oligonucleotides can be used for antibacterial and antiviral therapies by down-regulating undesirable proteins. PMOs have shown effectiveness in inhibiting bacterial growth and gene expression in E. coli and B. subtilis. These findings highlight the versatility of RNA-based therapeutics in treating a wide range of diseases.