Are we there yet with XNA aptamers?

Since their original development, aptamers (or nucleic acid oligomers of defined sequence that are capable of high-affinity and high-specificity binding to a target) have been heralded as possible and promising new therapeutic modalities. Increasingly versatile and customizable aptamer selection (SELEX) processes, alongside incorporation of novel synthetic nucleic acid (XNA) chemistries, have played a key role in the development of therapeutically relevant molecules. Nonetheless, despite the significant progress in the last 40 years, clinical applications of aptamers remain a nascent field. This review summarises some of the key developments in the field in the last 40 years, highlighting the progress made in aptamer selection, XNA chemistries and computational analyses. We discuss the intricacies and limitations of the current gold standard in aptamer SELEX and underscore the added complexities of XNA incorporation. Reflecting on the distinction between the antibody and aptamer fields, we advocate how a more mature understanding of this class of molecules could be driving the next generation of applications.