Targeted delivery of oligonucleotides to liver hepatocytes using 
N-acetylgalactosamine (GalNAc) conjugates that bind to the asialoglycoprotein 
receptor has become a breakthrough approach in the therapeutic oligonucleotide 
field. This technology has led to the approval of givosiran for the treatment of 
acute hepatic porphyria, and there are another seven conjugates in 
registrational review or phase 3 trials and at least another 21 conjugates at 
earlier stages of clinical development. This review highlights some of the 
recent chemical and preclinical advances in this space, leading to a large 
number of clinical candidates against a diverse range of targets in liver 
hepatocytes. The review focuses on the use of this delivery system for small 
interfering RNAs (siRNAs) and antisense molecules that cause downregulation of 
target mRNA and protein. A number of other approaches such as anti-microRNAs and 
small activating RNAs are starting to exploit the technology, broadening the 
potential of this approach for therapeutic oligonucleotide intervention.