Bus Tanja, Traeger Anja, Schubert Ulrich S
Laboratory of Organic Chemistry and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany.
J Mater Chem B. 2018 Nov 21;6(43):6904-6918. doi: 10.1039/c8tb00967h. Epub 2018 Sep 26.
The targeted and efficiency-oriented delivery of (therapeutic) nucleic acids raises hope for successful gene therapy, i.e., for the local and individual treatment of acquired and inherited genetic disorders. Despite promising achievements in the field of polymer-mediated gene delivery, the efficiency of the non-viral vectors remains orders of magnitude lower than viral-mediated ones. Several obstacles on the molecular and cellular level along the gene delivery process were identified, starting from the design and formulation of the nano-sized carriers up to the targeted release to their site of action. In particular, the efficient escape from endo-lysosomal compartments was demonstrated to be a major barrier and its exact mechanism still remains unclear. Different hypotheses and theories of the endosomal escape were postulated. The most popular one is the so-called "proton sponge" hypothesis, claiming an escape by rupture of the endosome through osmotic swelling. It was the first effort to explain the excellent transfection efficiency of poly(ethylene imine). Moreover, it was thought that a unique mechanism based on the ability to capture protons and to buffer the endosomal pH is the basis of endosomal escape. Recent theories deal with the direct interaction of the cationic polyplex or free polymer with the exoplasmic lipid leaflet causing membrane destabilization, permeability or polymer-supported nanoscale hole formation. Both escape strategies are more related to viral-mediated escape compared to the "proton sponge" effect. This review addresses the different endosomal release theories and highlights their key mechanism.
（治疗性）核酸的靶向性和高效递送为成功的基因治疗带来了希望，即针对获得性和遗传性遗传疾病进行局部和个体化治疗。尽管在聚合物介导的基因递送领域取得了令人鼓舞的成果，但非病毒载体的效率仍比病毒介导的载体低几个数量级。在基因递送过程中，从纳米级载体的设计和配方到其作用部位的靶向释放，在分子和细胞水平上发现了几个障碍。特别是，从内溶酶体区室有效逃逸被证明是一个主要障碍，其确切机制仍不清楚。人们提出了不同的内体逃逸假说和理论。最流行的是所谓的“质子海绵”假说，该假说认为内体通过渗透肿胀破裂而逃逸。这是首次尝试解释聚乙烯亚胺出色的转染效率。此外，人们认为基于捕获质子和缓冲内体pH值能力的独特机制是内体逃逸的基础。最近的理论涉及阳离子多聚体或游离聚合物与外质脂质小叶的直接相互作用，导致膜不稳定、通透性或聚合物支持的纳米级孔洞形成。与“质子海绵”效应相比，这两种逃逸策略都与病毒介导的逃逸更为相关。本综述阐述了不同的内体释放理论，并突出了它们关键的机制。
