Varga C M, Wickham T J, Lauffenburger D A
Division of Bioengineering & Environmental Health, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Biotechnol Bioeng. 2000 Dec 20;70(6):593-605. doi: 10.1002/1097-0290(20001220)70:6<593::aid-bit1>3.0.co;2-n.
One way to deliver transgenes to cells in a selective manner is to target the delivery vehicles, or vectors, to specific cell-surface receptors as a first step toward ultimate transport of the gene to the nucleus for expression. While selective delivery, although often to undesired cell types, occurs naturally for some viral vectors and can be achieved for nonviral vehicles, current understanding and control of the delivery mechanism is inadequate for many therapeutic applications. The complicated nature of receptor-mediated transgene uptake and transport requires improved analysis to more effectively evaluate delivery vehicles. As receptor-mediated pathways for gene delivery typically involve vector binding, internalization, subcellular trafficking, vesicular escape, nuclear translocation, and unpackaging for transcription, each of these processes offer mechanisms that can be exploited to enhance targeted gene delivery via properly designed vehicles. For the purpose of this review, current targeted gene delivery vehicles are divided into three approaches: viral, synthetic, and hybrid vectors. Each approach possesses advantages as well as disadvantages at the present time for in vitro and in vivo application, and provides particular challenges to overcome in order to gain significantly improved targeted delivery properties. Quantitative experiments and mathematical modeling of the gene delivery pathway will serve to provide insight into molecular mechanisms and rate-limiting steps for effective gene expression. Information on molecular mechanisms obtained by such methodologies can then be applied to specific vectors, whether viral, synthetic, or hybrid, allowing for the creation of targeted, effective, and safe gene therapeutics.
以选择性方式将转基因递送至细胞的一种方法是，作为基因最终转运至细胞核进行表达的第一步，将递送载体（即载体）靶向特定的细胞表面受体。虽然对于某些病毒载体而言，选择性递送（尽管通常是递送至非期望的细胞类型）是自然发生的，并且对于非病毒载体也可以实现，但目前对于递送机制的理解和控制在许多治疗应用中还不够充分。受体介导的转基因摄取和转运的复杂性质需要改进分析方法，以便更有效地评估递送载体。由于受体介导的基因递送途径通常涉及载体结合、内化、亚细胞运输、囊泡逃逸、核转位以及转录解包，这些过程中的每一个都提供了可通过合理设计的载体加以利用以增强靶向基因递送的机制。出于本综述的目的，当前的靶向基因递送载体分为三种方法：病毒载体、合成载体和杂交载体。目前，每种方法在体外和体内应用中都有优点和缺点，并且为了显著改善靶向递送特性，都面临着需要克服的特殊挑战。基因递送途径的定量实验和数学建模将有助于深入了解有效基因表达的分子机制和限速步骤。通过这些方法获得的关于分子机制的信息随后可应用于特定的载体，无论是病毒载体、合成载体还是杂交载体，从而能够创建靶向、有效且安全的基因疗法。
