Delivery architectures for oligonucleotide therapeutics in genetic and rare diseases: GalNAc-based hepatocyte targeting and extrahepatic translation.

Abstract

Many genetic and rare diseases are molecularly defined but remain difficult to treat because their biology involves intracellular targets, toxic gain-of-function mechanisms, splicing defects, repeat expansions, or chemically undruggable pathways. Although RNA medicines can be designed directly from genetic information, their clinical success depends on delivery architecture rather than sequence design alone. This review examines delivery architectures for oligonucleotide therapeutics, using GalNAc-siRNA as the central clinically validated model. The GalNAc-siRNA platform demonstrates how receptor selection, ligand presentation, linker design, chemical stabilization, intracellular persistence, PK/PD properties, dosing, and safety monitoring enable durable subcutaneous hepatocyte pharmacology. As of July 18, 2026, seven FDA-approved GalNAc-siRNA drugs validated this paradigm. We compare extrahepatic strategies for the CNS, muscle, eye, lung, kidney, immune cells, and adipose tissue. Intrathecal C16-siRNA and TfR1-directed antibody-oligonucleotide conjugates are among the most advanced extrahepatic approaches. Inhaled pulmonary RNAi has generated human PD and entered Phase 2a development; divalent CNS siRNA has entered Phase 1; adipose RNAi is in Phase 1/2a; ocular and kidney synthetic-siRNA platforms remain preclinical, whereas immune-cell delivery remains early translational. Antisense oligonucleotide and phosphorodiamidate morpholino oligomer examples illustrate shared delivery principles, including GalNAc-mediated hepatocyte targeting, TfR1-mediated muscle uptake, and local central nervous system and ocular administration. Rather than comprehensively reviewing oligonucleotide chemistry, this review emphasizes delivery architecture, including targeting moieties, lipophilic and structural handles, linker design, administration route, PK/PD, safety liabilities, rare-disease biomarkers, and regulatory experience. Overall, RNA medicines are genetically programmable, but their clinical reach is determined by delivery architecture.