Molecular Therapy Nucleic Acids · Mar 4, 2026

Enhanced liver-targeted delivery with ribofuranose-based GalNAc conjugates

By Pradeep SP, Ruchi R, Bahal R

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.

doi.org/10.1016/j.omtn.2026.102871Open accessPubMed 41810141Interventions