Liver-Specific Biocompatible Lipid Nanoparticle-Enabled mRNA Therapy for Haemophilia B.

The standard treatment for Haemophilia B (HB) involves frequent intravenous (IV) infusions of recombinant factor IX (FIX), which imposes a significant financial burden on patients. FIX delivery as messenger RNA using lipid nanoparticles (LNPs) presents a promising alternative, but achieving prolonged and effective protein expression remains challenging. To this end, we developed Galactosylated Lipid Nucleic Acid complex (GaLiNAx) to enhance the delivery of chemically modified FIX mRNAs. The nanocarrier encompasses an ionizable galactosylated lipid to enable receptor-mediated endocytosis and a transfection-competent cationic lipid for optimal mRNA complexation. We incorporated truncated albumin UTRs and base modifications in functional FIX mRNA to enhance hepatic translation. In an HB mouse model, GaLiNAx demonstrated therapeutically relevant FIX protein expression for about one month after single dose offering a cost-effective option. Safety assessments indicated that multiple doses of GaLiNAx could be administered without toxicity to any major organs. These results highlight the potential of long-lasting mRNA therapy as an effective protein replacement strategy for HB, paving the way for future mRNA therapeutics targeting other monogenic liver disorders.