Figure . Examples of terminal modifications for therapeutic RNAs. siRNA with 3' tripartite GalNAc ligand L96 (O in the blue circle can be replaced with S); ASO with a PMO backbone (black) and triethylene glycol; RNA aptamer with double 5'-PEGylation. In summary, chemical modifications protect therapeutic RNAs from exonucleases, endonucleases, and the cellular environment, and they enhance pharmaceutical activity. The choice of the backbone determines whether an ASO blocks cellular processes such as translation, transcription, or splicing or targets an RNA for nuclease digestion. The 2'-ribose modifications on siRNAs mitigate offtarget effects by lowering the thermal stability, thereby enhancing target-specific binding. 1methylpseudouridine improves stability and translation of therapeutic mRNAs. Since therapeutic RNAs are extensively modified, they frequently are not designated as RNA vs. DNA but have names such as ASO (antisense oligonucleotide) and siNA (short interfering nucleic acid) for siRNAs. RNA delivery systems RNA therapeutics, which are hydrophilic and negatively charged, cannot diffuse across cell membranes; thus, they require delivery vectors and/or chemical modification to reach their targets. When administered systemically, RNA delivery systems need to protect the RNA against serum nucleases, bypass the immune system, avoid non-specific interactions with serum proteins, and block renal clearance. While biological barriers such as immunogenicity and nucleases are usually addressed by modifying the RNA chemically, encapsulation of RNA into nanocarriers can both protect and deliver RNA to cells. 272 Nanomaterials of low toxicity, biodegradability, and biocompatibility are used as RNA carriers. These include lipids, chitosan, cyclodextrin, polyethyleneimine (PEI), poly(lactic-co-glycolic acid), dendrimers, magnetic nanoparticles, carbon nanotubes, gold nanoparticles, silica nanoparticles, and others (Figure ).