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. 2022 Jul 23;13(7):644. doi: 10.1038/s41419-022-05075-2

Fig. 2. Types of RNA-based therapeutics and modes of action.

Fig. 2

A Antisense oligonucleotides (ASOs) can modulate the target gene expression through two mechanisms. (①) In the occupancy-mediated degradation way, ASOs trigger the target mRNA cleavage by RNase H1 or ribozymes. The Occupancy-only mechanisms do not directly degrade target RNA. Instead, it regulates the gene expression in several ways: (②) alter RNA splicing using splice-switching ASOs to induce exon skipping or exon inclusion; (③) lead to nonsense-mediated mRNA decay (NMD); (④) inhibit or activate translation; (⑤) block the microRNAs binding to target mRNA. B RNA interference (RNAi). Long double-stranded RNA (dsRNA) and precursor microRNA (pre-miRNA) are processed by Dicer into short interfering RNA (siRNA). The antisense strand (indicated as a blue strand) of siRNA is loaded into the RNA-induced silencing complex (RISC) for RNA targeting, degradation or translation repression. C CRISPR/Cas-based RNA editing system includes two Cas nuclease categories, Cas9 and Cas13. A guide RNA(gRNA) binds to Cas9 to cleave ssRNA with (①) or without (②) the help of a protospacer-adjacent motif (PAM). (③) A single CRISPR RNA (crRNA) guides Cas13 to target specific RNA having a protospacer flanking sequence (PFS). (④) In addition to knockdown target RNA, a catalytically deactivated Cas13b (dCas9b) facilitates the A-to-I editing with ADAR. D RNA aptamers function as agonizts or delivery agents. (①) As an antagonist aptamer, Pegaptanib interacts explicitly with vascular endothelial growth factor (VEGF) to inhibit the interaction of VEGF with its receptors, thus treating macular degeneration. (②) Cell type-specific RNA aptamers deliver agents (miRNA, siRNA, shRNA, antibody and chemotherapy drugs) by linking to or conjugating. E mRNA vaccine. (①) The mRNA vaccine against SARS-CoV-2 (mRNA-1273) is delivered into antigen-presenting cells by lipid nanoparticle (LNP). (②)The mRNA encoding SARS-CoV-2 spike protein is released into the cytoplasm and translated to antigen protein by the ribosome. (③) Some antigen proteins are degraded into small peptides by the proteasome and presented to the surface of CD8+ T cells by major histocompatibility complex I (MHCI). The CD8+ cytotoxic T-cell-mediated immunity kills infected cells by secreting perforin or granzyme. (④) Other antigen proteins are degraded in the lysosome and displayed on the surface of T helper cells by MHC II. The B-cell/antibody-mediated humoral immunity uses antibodies to neutralize pathogens.