Targeted delivery with ligand conjugate
Conjugation attaches a targeting ligand directly to a nuclease-resistant siRNA, eliminating the need for an encapsulating particle.
The approach relies on three components:
- A high-capacity cell-surface receptor on the cell type of interest.
- A targeting ligand capable of binding with high affinity and specificity.
- A nuclease-resistant siRNA.
The breakthrough came with conjugation of a trivalent N-acetylgalactosamine (GalNAc) ligand, which targets the asialoglycoprotein receptor (ASGPR) abundant on liver hepatocytes, paired with metabolically stable siRNA. Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).