http://jcps.bjmu.edu.cn

Journal of Chinese Pharmaceutical Sciences ›› 2024, Vol. 33 ›› Issue (3): 189-200.DOI: 10.5246/jcps.2024.03.015

• Original articles •     Next Articles

Polymer-lipid nanoparticles enhance liver-targeted delivery of therapeutic base editor plasmid for the treatment of hereditary tyrosinemia type 1 (HT-1)

Datong Gao1, Meng Lin1,2, Yiwei Peng1, Jiajia Li1, Yiliang Yang1, Yulu Teng1, Siyu Chen1, Wen Sun1, Zinan Wu1, Quan Yuan1, Zhenzhen Yang1,3, Yanxia Zhou1, Xinru Li1, Xianrong Qi1,*()   

  1. 1 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
    2 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
    3 Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking University Third Hospital, Peking University, Beijing 100191, China
  • Received:2023-11-14 Revised:2023-12-08 Accepted:2024-01-13 Online:2024-03-31 Published:2024-03-31
  • Contact: Xianrong Qi
  • Supported by:
    Beijing Natural Science Foundation (Grant No. L202044), National Natural Science Foundation of China (Grants No. 82373806, 82373806).

Abstract:

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.

Key words: Hereditary tyrosinemia type 1, Base editor, Polymer-lipid nanoparticles, Transfection efficiency, Gene delivery

Supporting: