Aptamers are single-stranded oligonucleotides that mimic antibodies by folding into complex 3D shapes that non-covalently bind with high affinity and specificity to diverse targets. Aptamers have been selected against viruses, 2 proteins, polysaccharides, bacteria, toxins, peptides, small molecules, amino acids and whole cells. Like antibodies, the recognition capacity of aptamers can be harnessed for the development of diagnostics and therapeutic agents. Aptamers have advantages over antibodies in that they are selected in a chemically controlled environment, which does not rely on eliciting an immune response, their lower molecular weight improves pharmacokinetics, their precise synthesis is low cost and provides possibility for comprehensive chemical modification, and they have a longer shelf life. Theoretically, aptamers can be used as therapeutics in any disease, particularly those in which extracellular blockade of proteins is needed. The global aptamer market size is estimated to value USD242 million in 2022 and is expected to grow to USD524 million by 2027. Systematic Evolution of Ligands by EXponential Enrichment (SELEX) is the standard procedure used for selecting aptamers for a particular target. SELEX starts with a large library of oligonucleotides (up to 10 14 sequences), followed by rounds of selection consisting on separating binders from nonbinders, followed by PCR-based amplification, followed up with sequencing. Although thousands of aptamers targeting a broad range of targets have been generated by SELEX, outstanding aptamers that can be reliably used in biomedical and analytical applications are still limited because there are gaps in their performance including their specificity and affinity. To overcome these hurdles, researchers have been investigating methods to create aptamers using larger library sizes and with more complex structures. Non-natural modifications of nucleic acids are known to enhance aptamer affinity, and can be discovered by using enzymes which will accept modified nucleotide triphosphates (dN*TPs), however this results in uniform modification -for example, with all uridines displaying a cubane appendage -since information on variations of modification at the same type of base would be lost in PCR amplification. Alternatively, a codon system has been introduced, but again this does not allow the modifications to evolve independently of the base sequence. Systematic manual alterations of pre-selected aptamers has been reported, but is laborious. Selecting both the correct type and sequence of modifications amongst masses of possibilities, independent of the base sequence has not previously been achieved.