Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery,Molecular Pharmaceutics

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Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-08-08 , DOI: 10.1021/acs.molpharmaceut.1c00244
Kosuke Noguchi ₁ , Momoko Obuki ₁ , Haruka Sumi ₁ , Merlin Klußmann ₂ , Kenta Morimoto ₁ , Shinya Nakai ₁ , Takuya Hashimoto ₃ , Daisuke Fujiwara ₁ , Ikuo Fujii ₁ , Eiji Yuba ₃ , Tomoka Takatani-Nakase _{4,

5} , Ines Neundorf ₂ , Ikuhiko Nakase _{1,

6}

Affiliation

The antimicrobial protein CAP18 (approximate molecular weight: 18 000), which was first isolated from rabbit granulocytes, comprises a C-terminal fragment that has negatively charged lipopolysaccharide binding activity. In this study, we found that CAP18 (106–121)-derived (sC18)₂ peptides have macropinocytosis-inducible biological functions. In addition, we found that these peptides are highly applicable for use as extracellular vesicle (exosomes, EV)-based intracellular delivery, which is expected to be a next-generation drug delivery carrier. Here, we demonstrate that dimerized (sC18)₂ peptides can be easily introduced on EV membranes when modified with a hydrophobic moiety, and that they show high potential for enhanced cellular uptake of EVs. By glycosaminoglycan-dependent induction of macropinocytosis, cellular EV uptake in targeted cells was strongly increased by the peptide modification made to EVs, and intriguingly, our herein presented technique is efficiently applicable for the cytosolic delivery of the biologically cell-killing functional toxin protein, saporin, which was artificially encapsulated in the EVs by electroporation, suggesting a useful technique for EV-based intracellular delivery of biofunctional molecules.

中文翻译：

用抗菌蛋白 CAP18 衍生的细胞穿透肽修饰的巨胞饮作用诱导的细胞外囊泡用于有效的细胞内递送

首次从兔粒细胞中分离出的抗菌蛋白 CAP18（大约分子量：18 000）包含一个 C 末端片段，该片段具有带负电荷的脂多糖结合活性。在这项研究中，我们发现 CAP18 (106–121) 衍生的 (sC18) ₂肽具有巨胞饮诱导的生物学功能。此外，我们发现这些肽非常适合用作基于细胞外囊泡（exosomes，EV）的细胞内递送，有望成为下一代药物递送载体。在这里，我们证明二聚体 (sC18) ₂当用疏水部分修饰时，肽可以很容易地引入 EV 膜上，并且它们显示出增强 EV 细胞摄取的高潜力。通过糖胺聚糖依赖性诱导大胞饮作用，通过对 EV 进行的肽修饰，大大增加了靶细胞中的细胞 EV 摄取，有趣的是，我们在此提出的技术有效地适用于生物细胞杀伤功能性毒素蛋白皂草素的细胞溶质递送，通过电穿孔将其人工封装在EV中，这表明了一种基于EV的细胞内递送生物功能分子的有用技术。

更新日期：2021-09-06

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