Fluorinated lipid nanoparticle-mediated mRNA delivery enables high-fidelity base editing for therapeutic reversal of hereditary tyrosinemia

Intracellular delivery of base editors shows great promise for the treatment of genetic diseases caused by single-base mutations. While lipid nanoparticles (LNPs) represent a promising non-viral system for delivering single-base editor mRNA, the efficacy has been limited by inefficient endosomal escape and instability. To address these challenges, we engineered a fluorolipid-enhanced LNP system that synergizes fluorolipid-mediated endosomal escape with high nanoparticle stability. The optimized formulation demonstrated a significant improvement in the delivery of mRNA to the liver compared to conventional LNPs. Capitalizing on this system, we delivered haA3A-CBE-VA mRNA, a high-fidelity base editor optimized for methylated and GC-rich genomic regions to correct the pathogenic A-to-G mutation at the start codon of Fah in a hereditary tyrosinemia type I mouse model. This intervention restored functional Fah protein expression, rescued disease phenotypes including progressive weight loss and hepatocyte necrosis, and eliminated detectable off-target edits. Our findings establish fluorinated LNPs as an efficient and promising tool for mRNA delivery to enable precision base editing.