Although siRNAs, like miRNAs, use the RISC to degrade their target mRNAs, siRNAs bind to specific areas in the mRNA coding region. This target specificity makes them attractive as potential drugs, but off-target effects can negate this advantage. In order to minimize off-target effects, siRNAs are modified to decrease their thermal stability, increase their target specificity, and decrease the stability of their binding of the siRNA to mRNAs that are not an exact match to the intended target mRNA. These usually include 2'-O-methyl and 2'-MOE ribose modifications that introduce steric hindrance to decrease binding affinity (more discussion in chemical modification section below). One of the earliest therapeutic RNAs, ASOs, recognize and bind to complementary DNA or RNA sequences, including mutated sequences that may lead to disease. Upon binding to the mutated sequences, ASOs may facilitate proper mRNA splicing, prevent translation of a defective protein, or target RNAs for degradation. In therapeutic antibody-oligonucleotide conjugates (AOCs), the antibody targets the site of interest while carrying an ASO or a siRNA that acts on the targeted region. Conjugation of an ASO to an antibody to create an AOC improves the pharmacokinetics of the ASO in vivo by increasing tissue distribution and prolonging gene silencing in multiple tissues. The CRISPR-Cas system uses a guide RNA that is either a combination of a trans-activating CRISPR RNA (tracrRNA) and a CRISPR RNA (crRNA) or a joined single guide RNA (sgRNA). The guide RNA directs the CRISPR complex containing a Cas endonuclease to a specific site in the genome for cleavage. The ability of the CRISPR-Cas system to create directed double-stranded breaks in DNA allows the repair of genetic mutations. Changing the endonuclease activity of Cas can convert CRISPR-Cas to a system that nicks a single strand of the DNA or that deaminates a specific nucleotide. If the Cas endonuclease is inactivated, the system can simply bind to DNA to regulate transcription. Aptamers are structure-based rather than sequence-based ligands that neither hybridize with other nucleic acids nor produce proteins. They can be RNA, DNA, RNA/DNA combinations, or even proteins. In vitro systematic evolution of ligands by exponential enrichment (SELEX) is used to identify single-stranded RNA or DNA oligonucleotides with a high affinity for a target. Because their binding depends on their 3D structure, aptamers can bind a wide range of targets, including proteins, cells, microorganisms, chemical compounds, and other nucleic acids. Aptamers may also serve as delivery agents for siRNA in nanoparticles for cancer therapy. To measure the distribution of research effort using different types of RNA as therapeutics, vaccines, or diagnostics, the percentages of journal publications and patents for each type of RNA was determined from data in the CAS Content Collection (Figure ). miRNA and mRNA, the two most popular therapeutic RNAs in the journal and patent literature, can serve as drugs, disease biomarkers, and drug targets. Together with siRNA, they represent most of the therapeutic RNA patent activity. Approved RNA drugs include mRNAs, siRNAs, ASOs, and aptamers; these RNAs along with CRISPR RNAs and AOCs comprise most of the clinical candidates. thought to be a by-product of RNA splicing that may have a role in regulation as a miRNA sponge; (d) saRNA, which regulates gene transcription; and (e) exosomal RNA, which is contained in naturally occurring lipid vesicles called exosomes, which can cross the blood-brain barrier and appear to be vital for cell-to-cell communication, and which transport mainly miRNA. Based on the CAS Content Collection data for CRISPR RNA, miRNA, and mRNA used in vaccines, diagnostics, and therapeutics , only mRNA has substantial applications in vaccines (Figure ). However, both miRNA and mRNA have demonstrated their potential as therapeutics and diagnostics.