Ovchinnikova Leyla A, Terekhov Stanislav S, Ziganshin Rustam H, Bagrov Dmitriy V, Filimonova Ioanna N, Zalevsky Arthur O, Lomakin Yakov A
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia.
Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Pharmaceutics. 2021 May 21;13(6):768. doi: 10.3390/pharmaceutics13060768.
Delivering protein therapeutics specifically into target cells and tissues is a promising avenue in medicine. Advancing this process will significantly enhance the efficiency of the designed drugs. In this regard, natural membrane-based systems are of particular interest. Extracellular vesicles (EVs), being the bilayer lipid particles secreted by almost all types of cells, have several principal advantages: biocompatibility, carrier stability, and blood-brain barrier penetrability, which make them a perspective tool for protein therapeutic delivery. Here, we evaluate the engineered genetically encoded EVs produced by a human cell line, which allow efficient cargo loading. In the devised system, the protein of interest is captured by self-assembling structures, i.e., "enveloped protein nanocages" (EPN). In their turn, EPNs are encapsulated in fusogenic EVs by the overexpression of vesicular stomatitis virus G protein (VSV-G). The proteomic profiles of different engineered EVs were determined for a comprehensive evaluation of their therapeutic potential. EVs loading mediated by bio-safe Fos-Jun heterodimerization demonstrates an increased efficacy of active cargo loading and delivery into target cells. Our results emphasize the outstanding technological and biomedical potential of the engineered EV systems, including their application in adoptive cell transfer and targeted cell reprogramming.
将蛋白质治疗药物特异性地递送至靶细胞和组织是医学领域一个很有前景的途径。推进这一过程将显著提高设计药物的效率。在这方面,基于天然膜的系统尤其令人关注。细胞外囊泡(EVs)是几乎所有类型细胞分泌的双层脂质颗粒,具有几个主要优点:生物相容性、载体稳定性和血脑屏障穿透性,这使其成为蛋白质治疗递送的一个有前景的工具。在此,我们评估了由人类细胞系产生的经过基因工程改造的EVs,其能够实现高效的货物装载。在设计的系统中,感兴趣的蛋白质被自组装结构捕获,即“包膜蛋白纳米笼”(EPN)。反过来,通过水泡性口炎病毒G蛋白(VSV-G)的过表达,EPN被包裹在融合性EVs中。测定了不同工程化EVs的蛋白质组学图谱,以全面评估其治疗潜力。由生物安全的Fos-Jun异二聚化介导的EVs装载显示出活性货物装载和递送至靶细胞的效率提高。我们的结果强调了工程化EV系统的杰出技术和生物医学潜力,包括它们在过继性细胞转移和靶向细胞重编程中的应用。