期刊
JOURNAL OF CONTROLLED RELEASE
卷 341, 期 -, 页码 511-523出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2021.11.046
关键词
Gene therapy; Nuclear delivery; Endoplasmic reticulum-targeting; Caveolae-mediated pathway; Lysosomal escape
资金
- National Natural Science Foundation of China [82020108029, 81773667, 82073398]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZ202021]
- 111 Project from the Ministry of Education of China
- State Administration of Foreign Experts Affairs of China [B16046]
- Double First-class University Projects [CPU2018GF08, CPU2018GY06]
- Key Research and Development Program of Jiangsu Province [BE2018742]
- Project of State Key Laboratory of Pathogenesis, Xinjiang Medical University [SKL-HIDCA-2019-7]
The study introduces a gene vector named CA(3)S(2) designed to enhance gene delivery efficiency by integrating and streamlining intracellular pathways for nuclear targeting. The optimized structure of the vector enhances ER targeting strategy, improving gene delivery efficacy.
The essential challenge of gene therapy is to develop safe and efficient vectors that escort genes to target sites. However, due to the cumbersome workflow of gene transfection into cells, successive gene loss occurs. This leads to considerable reductions in nuclear gene uptake, eventually causing low gene expression. Herein, we designed a gene vector named CA(3)S(2) (C: N,N'-cystamine-bis-acrylamide [CBA], A: agmatine dihydrochloride [Agm], S: 4-(2-aminoethyl) benzenesulfonamide [ABS]) with excellent gene transfection ability. This vector can promote gene delivery to the nucleus via enhanced endoplasmic reticulum (ER) targeting through integrating and streamlining of the complex intracellular pathway. Briefly, ABS endowed CA(3)S(2)/DNA nanoparticles with not only a natural ER-targeting tendency attributed to the caveolae-mediated pathway but also direct receptor binding capacity on the ER surface. Agm enabled CA(3)S(2) to enhance lysosomal escape and nuclear uptake ability. The gene delivery efficiency of CA(3)S(2) was significantly better than that of polyethyleneimine 25K (PEI 25K). Therefore, CA(3)S(2) is a promising gene carrier, and the ER-targeting strategy involving intracellular pathway integration and streamlining has potential for gene therapy.
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