State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China.
J Control Release. 2022 Jan;341:511-523. doi: 10.1016/j.jconrel.2021.11.046. Epub 2021 Dec 2.
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 CAS (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 CAS/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 CAS to enhance lysosomal escape and nuclear uptake ability. The gene delivery efficiency of CAS was significantly better than that of polyethyleneimine 25K (PEI 25K). Therefore, CAS is a promising gene carrier, and the ER-targeting strategy involving intracellular pathway integration and streamlining has potential for gene therapy.
基因治疗的根本挑战是开发安全有效的载体，将基因运送到靶位。然而，由于基因转染到细胞中的繁琐工作流程，连续的基因丢失会发生。这导致核基因摄取显著减少，最终导致低基因表达。在此，我们设计了一种名为 CAS（C：N，N'-胱胺双丙烯酰胺[CBA]，A：胍丁胺二盐酸盐[Agm]，S：4-（2-氨乙基）苯磺酰胺[ABS]）的基因载体，具有优异的基因转染能力。该载体可以通过整合和简化复杂的细胞内途径，通过增强内质网（ER）靶向来促进基因传递到细胞核。简而言之，ABS 赋予 CAS/DNA 纳米颗粒不仅具有天然的内质网靶向倾向归因于小窝介导途径，而且具有内质网表面的直接受体结合能力。Agm 使 CAS 能够增强溶酶体逃逸和核摄取能力。CAS 的基因传递效率明显优于聚乙烯亚胺 25K（PEI 25K）。因此，CAS 是一种很有前途的基因载体，涉及细胞内途径整合和简化的内质网靶向策略有可能用于基因治疗。
