Advancing liver gene therapy: Enhanced transduction with GalNAc-bioconjugated rAAV capsids.

This study explores a novel strategy to enhance liver-targeted gene delivery, crucial for treating metabolic disorders. While AAV-based gene therapy holds promise, high vector doses raise safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. Optimizing capsids to improve hepatocyte transduction efficiency is key to reducing these risks. We employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), highly expressed on hepatocytes. Covalent attachment of GalNAc-derived ligands to rAAV2 capsids significantly improved in vivo liver transduction, increasing GFP expression up to threefold. Immunohistochemical co-labeling confirmed exclusive transgene expression in hepatocytes, ensuring specificity. These findings highlight bioconjugation as a promising approach to enhance liver gene therapy while improving safety by lowering vector doses and off-target effects.