siRNA therapeutics: from hepatic delivery to extrahepatic targeting

INTRODUCTION: Small interfering RNA (siRNA) has progressed from an experimental gene-silencing tool to an established therapeutic modality through advances in chemical modification and delivery. Lipid nanoparticles (LNP) and N-acetylgalactosamine (GalNAc)-siRNA conjugates have driven this clinical translation, particularly for liver-directed applications. Extending comparable delivery efficiency and selectivity to non-hepatocyte cell populations and extrahepatic tissues remains a major challenge. AREAS COVERED: This review examines approved and late-stage siRNA therapeutics and the delivery principles underlying their clinical development. Relevant publications and clinical trial records from 1998 to 2026 were identified through PubMed and ClinicalTrials.gov, supplemented by regulatory agency reports. LNP-based delivery, GalNAc-mediated hepatocyte targeting, and emerging strategies for non-parenchymal liver cells and extrahepatic tissues are discussed, with emphasis on the factors governing cell-selective and productive delivery. Next-generation delivery technologies and the therapeutic distinctions between siRNA and antisense oligonucleotides are also considered. EXPERT OPINION: The next phase of siRNA therapeutics will require a transition from organ-level accumulation toward functional cell-selective delivery. Improved receptor targeting, intracellular trafficking, and endosomal escape, together with rationally designed delivery systems, may extend RNA interference beyond hepatocytes and broaden its therapeutic applications in inflammatory, fibrotic, metabolic, and malignant diseases.