Enhanced liver-targeted delivery with ribofuranose-based GalNAc conjugates

  • Mol Ther Nucleic Acids. 2026 Mar 4;37(1):102871. doi: 10.1016/j.omtn.2026.102871.
Sai Pallavi Pradeep  1 ,  Ruchi Ruchi  1 ,  Raman Bahal  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
PMID: 41810141 DOI: 10.1016/j.omtn.2026.102871
Abstract

This study highlights that small geometric constraints with the GalNAc moiety can tune receptor engagement and serum stability. The ribofuranose ring is a 2'-O-methyl modification, used in the siRNA backbone to improve metabolic stability and reduce nuclease susceptibility.8 The constrained ribofuranose conformation introduced into GalNAc increased serum stability and hepatic parenchymal clearance, thereby increasing systemic exposure. They also demonstrate the kilogram-scale synthesis of the G5 GalNAc-CPG support, making it feasible for manufacturing. PCSK9 is an ideal benchmark target as it is clinically validated, and the observed performance can be applied to Other hepatocyte-expressed genes. The inc-G5 GalNAc has progressed to phase 1 trials in China for PCSK9- and AGT-targeting siRNA. In a non-human primate study, inc-G5 GalNAc-siRNA conjugates showed a safety profile consistent with established GalNAc-siRNA (inc-L96) conjugates. A comparison of toxicology in AGT-targeting siRNA versus zilebesiran showed similar clinical chemistry and histopathology, supporting inc-G5 GalNAc as a potent, clinically translatable GalNAc delivery scaffold.

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