Polymer-lipid nanoparticles enhance liver-targeted delivery of therapeutic base editor plasmid for the treatment of hereditary tyrosinemia type 1(HT-1)
Hereditary tyrosinemia type 1(HT-1)is a rare autosomal recessive genetic disease with no effective cure at present.In recent years,gene-editing techniques such as base editor(BE)have been explored for treating HT-1.However,the delivery of nucleic acids faces challenges due to existing physiological barriers.In the present study,we constructed an asialoglycoprotein receptor(ASGPR)-targeted polymer-lipid nanoparticle to enhance the delivery efficiency of therapeutic nucleic acids for HT-1.To deliver BE plasmids,a biodegradable cationic polymer,acrylate-amino alcohol copolymer was synthesized and demonstrated superior transfection efficiency compared to the commercially available transfection reagent,Hieff TransTM.Subsequently,DOPE-PEG-GalNAc was combined with copolymer nanoparticles to enhance the hepatocyte delivery of the nanoparticles.Upon loading the recombinant BE plasmid,Fah-pCMV-ABE6.3-EGFP,the polymer-lipid nanoparticles exhibited remarkable hepatocyte selectivity,with a transfection efficiency over 70-fold higher than that of the free plasmid.The study suggested that polymer-lipid nanoparticles,in combination with liver-targeted ligands,could effectively enhance the liver-targeted delivery of therapeutic BE plasmids,providing a promising vector for gene therapy of HT-1.
Hereditary tyrosinemia type 1Base editorPolymer-lipid nanoparticlesTransfection efficiencyGene delivery
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