The clinical potential of l-oligonucleotides: challenges and opportunities

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.