Rewriting hepatic fate: emerging gene therapy strategies for liver disease

Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.