The hydroxyl group on the C-2' position of the ribose destabilizes RNA compared to DNA. Modification of this hydroxyl protects against nuclease digestion and can lower the thermal stability of duplexes formed with a target RNA. Figure In addition, the 5' and 3' ends of RNA can be modified using cleavable linkers attached to GalNAc groups or lipophilic moieties to target the therapeutic RNA to the desired tissue. The linkers are cleaved by acid pH, redox potential, or degradative enzymes in cells but not in serum or blood. Cleavable linkers include acid-cleavable groups, ester-based cleavable groups, and peptide-based cleavable groups.