Advances in RNA delivery to extrahepatic tissues and cells

Despite their transformative potential in treating genetic, neurological, and oncological disorders, the clinical application of RNA therapeutics remains largely confined to the liver. Current approved platforms rely on two fundamentally distinct hepatic delivery mechanisms. N-acetylgalactosamine (GalNAc) conjugation achieves liver targeting through designed, high-affinity binding to the asialoglycoprotein receptor on hepatocytes, while lipid nanoparticles (LNPs) accumulate in the liver through intrinsic physicochemical tropism driven by apolipoprotein adsorption and the fenestrated hepatic vasculature. Extending RNA delivery beyond the liver demands solutions to challenges that have no hepatic parallel, including formidable tissue-specific physiological barriers, critically low endosomal escape efficiencies, and the absence of any extrahepatic receptor-ligand system matching the efficiency and recyclability of the GalNAc-ASGPR axis. In this review, we critically examine recent progress in engineering delivery systems to access representative extrahepatic tissues, including the central nervous system(CNS), eye, lung, heart, spleen, inner ear, and bone marrow. We evaluate the rational design of viral vectors, polymeric and lipid-based nanocarriers, exosome platforms, hydrogel depot systems, and local administration strategies that bypass systemic clearance. By analyzing the molecular mechanisms, translational milestones, and persisting limitations of these approaches, this review identifies the key scientific and engineering bottlenecks that must be resolved to advance extrahepatic RNA therapeutics from preclinical promise toward broad clinical reality.