Advances in therapeutic oligonucleotide conjugates

Abstract Oligonucleotide therapeutics (ONTs) have revolutionized the medical landscape by enabling the precise modulation of genetic pathways. This perspective highlights the major conjugation strategies for ONTs, using antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) as representative modalities. We describe diverse classes of targeting ligands, including small molecules, cell-penetrating peptides (CPPs), antibodies, and aptamers. For example, triantennary N -acetylgalactosamine (GalNAc) conjugation has enabled a number of approved oligonucleotide therapeutics. Meanwhile, other emerging conjugation technologies have expanded oligonucleotide delivery to extrahepatic tissues to address a broader range of diseases. We further summarize the clinical translation of these delivery platforms, highlighting approved therapeutics alongside emerging clinical candidates. Finally, we provide an outlook on challenges and opportunities for the next generation of oligonucleotide therapeutics.