Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
Department of Pathology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
Exp Biol Med (Maywood). 2021 Feb;246(3):260-274. doi: 10.1177/1535370220965985. Epub 2020 Nov 12.
Delivery of genetic material to tissues is an important technique used in research settings and is the foundation upon which clinical gene therapy is built. The lung is a prime target for gene delivery due to a host of genetic, acquired, and infectious diseases that manifest themselves there, resulting in many pathologies. However, the delivery of genetic material to the lung remains a practical problem clinically and is considered the major obstacle needed to be overcome for gene therapy. Currently there are four main strategies for gene delivery to the lung: viral vectors, liposomes, nanoparticles, and electroporation. Viral delivery uses several different genetically modified viruses that enter the cell and express desired genes that have been inserted to the viral genome. Liposomes use combinations of charged and neutral lipids that can encapsulate genetic cargo and enter cells through endogenous mechanisms, thereby delivering their cargoes. Nanoparticles are defined by their size (typically less than 100 nm) and are made up of many different classes of building blocks, including biological and synthetic polymers, cell penetrant and other peptides, and dendrimers, that also enter cells through endogenous mechanisms. Electroporation uses mild to moderate electrical pulses to create pores in the cell membrane through which delivered genetic material can enter a cell. An emerging fifth category, exosomes and extracellular vesicles, may have advantages of both viral and non-viral approaches. These extracellular vesicles bud from cellular membranes containing receptors and ligands that may aid cell targeting and which can be loaded with genetic material for efficient transfer. Each of these vectors can be used for different gene delivery applications based on mechanisms of action, side-effects, and other factors, and their use in the lung and possible clinical considerations is the primary focus of this review.
将遗传物质递送到组织中是一种在研究环境中使用的重要技术，也是临床基因治疗的基础。由于在肺部表现出的多种遗传、获得性和传染性疾病，肺部是基因递送的主要靶标，导致许多病理学发生。然而，将遗传物质递送到肺部在临床上仍然是一个实际问题，被认为是基因治疗需要克服的主要障碍。目前，有四种主要的基因递送到肺部的策略：病毒载体、脂质体、纳米颗粒和电穿孔。病毒传递使用几种不同的遗传修饰病毒，这些病毒进入细胞并表达已插入病毒基因组的所需基因。脂质体使用带电荷和不带电荷的脂质的组合，这些脂质可以包裹遗传货物，并通过内源性机制进入细胞，从而递送其货物。纳米颗粒由其大小（通常小于 100nm）定义，由许多不同类别的构建块组成，包括生物和合成聚合物、穿透细胞的肽和其他肽以及树枝状聚合物，它们也通过内源性机制进入细胞。电穿孔使用温和到中度的电脉冲在细胞膜上创建孔，通过这些孔可以将递送到的遗传物质进入细胞。一种新兴的第五类，外泌体和细胞外囊泡，可能具有病毒和非病毒方法的优势。这些细胞外囊泡从包含受体和配体的细胞膜上芽生，这些受体和配体可能有助于细胞靶向，并且可以装载遗传物质以进行有效的转移。这些载体中的每一种都可以根据作用机制、副作用和其他因素用于不同的基因递送应用，它们在肺部的应用和可能的临床考虑是本综述的主要重点。
