The clinical potential of <scp>l</scp>-oligonucleotides: challenges and opportunities
Victoria Shearer, Chen‐Hsu Yu, Xuan Han, Jonathan T. Sczepanski
Abstract
Chemically modified nucleotides are central to the development of biostable research tools and oligonucleotide therapeutics. In this context, l-oligonucleotides, the synthetic enantiomer of native d-nucleic acids, hold great promise. As enantiomers, l-oligonucleotides share the same physical and chemical properties as their native counterparts, yet their inverted l-(deoxy)ribose sugars afford them orthogonality towards the stereospecific environment of biology. Notably, l-oligonucleotides are highly resistant to degradation by cellular nucleases, providing them with superior biostability. As a result, l-oligonucleotides are being increasingly utilized for the development of diverse biomedical technologies, including molecular imaging tools, diagnostic biosensors, and aptamer-based therapeutics. Herein, we present recent such examples that highlight the clinical potential of l-oligonucleotides. Additionally, we provide our perspective on the remaining challenges and practical considerations currently associated with the use of l-oligonucleotides and explore potential solutions that will lead to the broader adoption of l-oligonucleotides in clinical applications.