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 -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.