Hepatocyte targeting via the asialoglycoprotein receptor

Abstract

This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.

Fig. 1. A. Structures and binding affinities of natural ASGPR ligands Gal (1) and GalNAc (2). B. Triantennary GalNAc ligand 3 built on Tris scaffold. C. Monovalent synthetic ASGPR ligands and their binding affinities.

Fig. 2. A. Design of GalNAc–siRNA conjugates: STC – standard template chemistry, ESC – extended stabilization chemistry, ESC+ – extended stabilization chemistry plus, Silence platform – single GalNAc positioned at opposite sides of the sense strand. The top strand is the sense strand and the bottom is the antisense strand. B. Sirnaomics platform based on mxRNA and Dicerna's GalXC™ platform (passenger strand with tetraloop hairpin, ca. 36 bases, guide strand complementary to target mRNA, ca. 22 bases). C. Structure of monovalent GalNAc ligand built on serinol scaffold. Reproduced from ref. with permission from the Royal Society of Chemistry, copyright 2023.

Fig. 3. Mechanism of action of siRNA–GalNAc conjugates. Reproduced from ref. with permission from the Royal Society of Chemistry, copyright 2023.