Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, de Boelelaan 1117HV Amsterdam, The Netherlands.
Adv Drug Deliv Rev. 2013 Mar;65(3):348-56. doi: 10.1016/j.addr.2012.07.006. Epub 2012 Jul 20.
A major goal in biomedical research is to clinically reverse the cause of disease rather than treating the symptoms. Gene therapy has the potential to meet this goal and the discovery of RNA interference (RNAi) has lead to a new class of highly selective therapeutics. However, initial enthusiasm is reduced due to safety concerns associated with virus-based delivery vectors that are used for in vivo delivery. Viral vectors for siRNA delivery into target cells are used because of their high target specificity and delivery efficacy (endosomal escape). Recent discoveries suggest that a specialized form of nano-sized lipid vesicles called exosomes can incorporate and transport functional RNAs into target cells and may serve as an attractive alternative. Evidence is accumulating that most pluricellular organisms sustain exosome-based communications via inter-cellular exchange of mRNA and miRNAs between cells. We discovered that viruses have found ways to exploit this communication pathway and we argue here that adaptations of exosomes imposed by viruses maybe exploited for superior delivery of RNA in vivo. We discuss recent discoveries in exosome biogenesis their physical properties, targeting and delivery strategies and how the knowledge of exosome production in virus infected cells could propel their entry into clinical settings.
生物医学研究的一个主要目标是临床逆转疾病的原因,而不是治疗症状。基因治疗有可能实现这一目标,而 RNA 干扰 (RNAi) 的发现则带来了一类新的高度选择性治疗药物。然而,由于与用于体内递送的基于病毒的递送载体相关的安全问题,最初的热情有所降低。用于将 siRNA 递送至靶细胞的病毒载体因其高靶特异性和递送功效(内体逃逸)而被使用。最近的发现表明,一种称为外体的特殊形式的纳米大小脂质囊泡可以将功能性 RNA 纳入并运送到靶细胞中,并且可能成为一种有吸引力的替代方法。越来越多的证据表明,大多数多细胞生物通过细胞间 mRNA 和 miRNA 的交换来维持基于外体的通讯。我们发现病毒已经找到了利用这种通讯途径的方法,我们在这里认为,病毒对外体的适应性改造可能被利用来提高 RNA 在体内的递送效率。我们讨论了外体生物发生的最新发现,包括它们的物理性质、靶向和递送策略,以及病毒感染细胞中外体产生的知识如何推动它们进入临床环境。