Aptamers have ester linkages to protective groups and can have extensive sugar-phosphate backbone modifications, such as PEGylation (the covalent attachment of polyethylene glycol) on their 5' ends. Because aptamers bind to their targets as a result of their tertiary structure and do not rely on nucleic acid hybridization for function, they have fewer constraints on modifications compared to other therapeutic RNAs. The single FDA-approved aptamer, Macugen, has extensive 2'-O-methyl and 2'- fluoro modifications, a 3'-to-3' link to thymidine at its 3' end, as well as double PEGylation at its 5' end (Figure ).