RNA interference (RNAi) has rapidly matured as a novel therapeutic approach. In this field, chemical modifications have been critical to the clinical success of short interfering RNAs (siRNAs). Notwithstanding the significant advances, achieving robust durability and gene silencing in extrahepatic tissues, as well as reducing off-target effects of siRNA, are areas where chemical modifications can still improve siRNA performance. The present study developed the challenging synthesis of amide-linked guanosine dimers (G