1. Polymer-lipid nanoparticles enhance liver-targeted delivery of therapeutic base editor plasmid for the treatment of hereditary tyrosinemia type 1 (HT-1).
- Author
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Datong Gao, Meng Lin, Yiwei Peng, Jiajia Li, Yiliang Yang, Yulu Teng, Siyu Chen, Wen Sun, Zinan W1, Quan Yu, Zhenzhen Yang, Yanxia Zhou, Xinru Li, and Xianrong Qi
- Subjects
NANOPARTICLES ,NUCLEIC acids ,POLYMERS ,GENE therapy ,CATIONIC polymers ,GENE transfection ,PLASMIDS - Abstract
Hereditary tyrosinemia type 1 (HT-1) is a rare autosomal recessive genetic disease with no effective cure at presen t. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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