Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems. Molecules 2020, 25, 3 2 of 51 molecules [2]. Nowadays, the aptamer field covers various biomedical applications, including [3], therapeutic [4-6], aptasensors [7], biosensors [8,9], diagnostic [10,11], and imaging systems [12].Aptamers need to be stabilized for in vivo use against nuclease degradation, and their small size makes them susceptible to renal filtration. Aptamers' stabilization can be attained by chemically modifying them using different approaches. Moreover, introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [12]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology [1].Chemical modifications of aptamer oligonucleotides are needed mainly to enhance their resistance to nuclease degradation and lowering their renal filtration. Additionally, chemical modifications, in some cases, may increase the aptamer-binding affinity [13]. Many approaches have been introduced to promote the stability of aptamers without altering their binding affinity and specificity against their targets. These approaches include chemical modification of the phosphate...
