Beyond GalNAc! Drug delivery systems comprising complex oligosaccharides for targeted use of nucleic acid therapeutics

Nucleic Acid Therapeutics (NATs) are establishing a leading role for the management and treatment of genetic diseases following FDA approval of nusinersen, patisiran, and givosiran in the last 5 years, the breakthrough of milasen, with more approvals undoubtedly on the way. Givosiran takes advantage of the known interaction between the hepatocyte specific asialoglycoprotein receptor (ASGPR) and N-acetyl galactosamine (GalNAc) ligands to deliver a therapeutic effect, underscoring the value of targeting moieties. In this review, we explore the history of GalNAc as a ligand, and the paradigm it has set for the delivery of NATs through precise targeting to the liver, overcoming common hindrances faced with this type of therapy. We describe various complex oligosaccharides (OSs) and ask what others could be used to target receptors for NAT delivery and the opportunities awaiting exploration of this chemical space.

Automated summary

Nucleic Acid Therapeutics (NATs) have gained importance in the management and treatment of genetic diseases. Givosiran, which takes advantage of the interaction between ASGPR and GalNAc, highlights the value of targeted moieties. Through exploring the history of GalNAc as a ligand and identifying other potential oligosaccharides for NAT delivery, this review provides opportunities for further research.