Strategic design of GalNAc-helical peptide ligands for efficient liver targeting

There is a growing need for liver-selective drug delivery systems (DDS) in the treatment and diagnosis of liver diseases. The asialoglycoprotein receptor, a trimeric protein specifically expressed in the liver, is a key target for DDS. We hypothesized that peptides with reduced main-chain flexibility and strategically positioned N-acetylgalactosamine (GalNAc) moieties could enhance liver selectivity and uptake efficiency. The helical peptides designed in this study demonstrated superior uptake efficiency and liver selectivity compared with the conventional triantennary GalNAc DDS. These peptides also showed potential in protein delivery. Furthermore, we explored their application in lysosome-targeting chimeras (LYTACs), gaining valuable insights into the requirements for effective LYTAC functionality. This study not only highlights the potential of helical peptides as liver-selective DDS ligands, but also opens avenues for their use in various therapeutic and diagnostic applications, making significant strides in the targeted treatment of liver diseases.