Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery

Nakase, Ikuhiko; Noguchi, Kosuke; Aoki, Ayako; Takatani‐Nakase, Tomoka; Fujii, Ikuo; Futaki, Shiroh

doi:10.1038/s41598-017-02014-6

Cited by 140 publications

(158 citation statements)

References 40 publications

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“…Arginine-rich peptides have shown to have this effect on the cellular signal transduction via syndecan multimerization. Multimerization of syndecan-4 was observed in the presence of R8, followed by an increase in the internalized amount of the peptide [71,72]. All of the aforementioned interactions lead to the internalization of arginine-rich peptides by the activation of Rac protein.…”

Section: Macropinocytosis As An Entry Mechanismmentioning

confidence: 95%

Internalization mechanisms of cell-penetrating peptides

Ruseska

Zimmer

2020

Beilstein J. Nanotechnol.

287

264

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In today’s modern era of medicine, macromolecular compounds such as proteins, peptides and nucleic acids are dethroning small molecules as leading therapeutics. Given their immense potential, they are highly sought after. However, their application is limited mostly due to their poor in vivo stability, limited cellular uptake and insufficient target specificity. Cell-penetrating peptides (CPPs) represent a major breakthrough for the transport of macromolecules. They have been shown to successfully deliver proteins, peptides, siRNAs and pDNA in different cell types. In general, CPPs are basic peptides with a positive charge at physiological pH. They are able to translocate membranes and gain entry to the cell interior. Nevertheless, the mechanism they use to enter cells still remains an unsolved piece of the puzzle. Endocytosis and direct penetration have been suggested as the two major mechanisms used for internalization, however, it is not all black and white in the nanoworld. Studies have shown that several CPPs are able to induce and shift between different uptake mechanisms depending on their concentration, cargo or the cell line used. This review will focus on the major internalization pathways CPPs exploit, their characteristics and regulation, as well as some of the factors that influence the cellular uptake mechanism.

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Section: Macropinocytosis As An Entry Mechanismmentioning

confidence: 95%

Internalization mechanisms of cell-penetrating peptides

Ruseska

Zimmer

2020

Beilstein J. Nanotechnol.

287

264

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“…To enhance cellular uptake of EVs, Nakase et al used active EV engineering to modify EV membranes. Expression of modified arginine-rich cell-penetrating peptides resulted in activation of the macropinocytosis pathway, causing an increase in cellular EV uptake (128). Additionally, active EV modification can be used to modify circulation clearance and improve targeted uptake.…”

Section: Direct Ev Modificationmentioning

confidence: 99%

Therapeutic Potential of Engineered Extracellular Vesicles

Mentkowski

Snitzer

Rusnak

et al. 2018

AAPS J

147

117

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Extracellular vesicles (EVs) comprise a heterogeneous group of small membrane vesicles, including exosomes, which play a critical role in intracellular communication and regulation of numerous physiological processes in health and disease. Naturally released from virtually all cells, these vesicles contain an array of nucleic acids, lipids and proteins which they transfer to target cells within their local milieu and systemically. They have been proposed as a means of "cell-free, cell therapy" for cancer, immune disorders, and more recently cardiovascular disease. In addition, their unique properties of stability, biocompatibility, and low immunogenicity have prompted research into their potential as therapeutic delivery agents for drugs and small molecules. In this review, we aim to provide a comprehensive overview of the current understanding of extracellular vesicle biology as well as engineering strategies in play to improve their therapeutic potential.

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“…Recently, several regimens have been tested to produce hybrid EVs upon fusion with synthetic lipid nanoparticles. This membrane-engineering approach is based on freeze-thaw-induced fusion of EV membranes with lipids of synthetic nanoparticles [ 192 ]. The drawback is related to the increased toxicity of mixed nanoparticles, as well as potentially reduced ability to cross biological barriers (e.g., endothelial barrier or endolysosomal degradation) due to their increased size and altered composition [ 193 ].…”

Section: Engineering the Surface Of Evs For Improved And Targeted mentioning

confidence: 99%

Gene Editing by Extracellular Vesicles

Kostyushev

Kostyusheva

Brezgin

et al. 2020

IJMS

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CRISPR/Cas technologies have advanced dramatically in recent years. Many different systems with new properties have been characterized and a plethora of hybrid CRISPR/Cas systems able to modify the epigenome, regulate transcription, and correct mutations in DNA and RNA have been devised. However, practical application of CRISPR/Cas systems is severely limited by the lack of effective delivery tools. In this review, recent advances in developing vehicles for the delivery of CRISPR/Cas in the form of ribonucleoprotein complexes are outlined. Most importantly, we emphasize the use of extracellular vesicles (EVs) for CRISPR/Cas delivery and describe their unique properties: biocompatibility, safety, capacity for rational design, and ability to cross biological barriers. Available molecular tools that enable loading of desired protein and/or RNA cargo into the vesicles in a controllable manner and shape the surface of EVs for targeted delivery into specific tissues (e.g., using targeting ligands, peptides, or nanobodies) are discussed. Opportunities for both endogenous (intracellular production of CRISPR/Cas) and exogenous (post-production) loading of EVs are presented.

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Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery

Cited by 140 publications

References 40 publications

Internalization mechanisms of cell-penetrating peptides

Internalization mechanisms of cell-penetrating peptides

Therapeutic Potential of Engineered Extracellular Vesicles

Gene Editing by Extracellular Vesicles

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