RNAi delivery by exosome-mimetic nanovesicles – Implications for targeting c-Myc in cancer

Lunavat, Taral R.; Jang, Su Chul; Nilsson, Lisa M.; Park, Hyun Taek; Repiská, Gabriela; Lässer, Cecilia; Nilsson, Jonas A.; Gho, Yong Song; Lötvall, Jan

doi:10.1016/j.biomaterials.2016.06.024

Cited by 198 publications

(154 citation statements)

References 40 publications

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“…40 The amount of miR-26a loaded into purified exosomes was evaluated using a qRT-PCR assay. A calibration curve was established for the qRT-PCR assay using known amounts of pure miR-26a in a set of serially diluted samples.…”

Section: Quantification Of Mir-26 Loading Into Exosomementioning

confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

233

152

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Introduction Exosomes are closed-membrane nanovesicles that are secreted by a variety of cells and exist in most body fluids. Recent studies have demonstrated the potential of exosomes as natural vehicles that target delivery of functional small RNA and chemotherapeutics to diseased cells. Methods In this study, we introduce a new approach for the targeted delivery of exosomes loaded with functional miR-26a to scavenger receptor class B type 1-expressing liver cancer cells. The tumor cell-targeting function of these engineered exosomes was introduced by expressing in 293T cell hosts, the gene fusion between the transmembrane protein of CD63 and a sequence from Apo-A1. The exosomes harvested from these 293T cells were loaded with miR-26a via electroporation. Results The engineered exosomes were shown to bind selectively to HepG2 cells via the scavenger receptor class B type 1–Apo-A1 complex and then internalized by receptor-mediated endocytosis. The release of miR-26a in exosome-treated HepG2 cells upregulated miR-26a expression and decreased the rates of cell migration and proliferation. We also presented evidence that suggest cell growth was inhibited by miR-26a-mediated decreases in the amounts of key proteins that regulate the cell cycle. Conclusion Our gene delivery strategy can be adapted to treat a broad spectrum of cancers by expressing proteins on the surface of miRNA-loaded exosomes that recognize specific biomarkers on the tumor cell.

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Section: Quantification Of Mir-26 Loading Into Exosomementioning

confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

233

152

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“…The lysis of extracellular vesicles and protein estimation was carried out using RIPA buffer and the BCA Protein Assay Kit (Pierce, Thermo Scientific) as described previously (5,32). The primary antibodies used were Melan-A (1:1,000 dilution), Calnexin (1:1,000), CD81 (1:1,000), Bcl-2 (1:1,000), GAPDH (1:1,000), and BRAF (1:1,000) from Santa Cruz Biotechnology; TSG-101 (1:1,000; clone 4A10) from Abcam; c-Myc (1:1,000), β-actin (1:1,000), pERK1/2 (1:1,000), total ERK1/2 (1:1,000), and MITF (1:1,000) from Cell Signaling Technology; and BRAF V600E (1:1,000) from Spring Biosciences.…”

Section: Methodsmentioning

confidence: 99%

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Lunavat

Cheng

Einarsdottir

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF V600 mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p upregulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.small RNAs | extracellular vesicles | cancer | noncoding RNAs

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“…Although EVMs exhibit characteristics extremely similar to Exos,53, 54, 124 the actual identity of EVMs needs to be clarified by further investigation.…”

Section: High‐yield Tactics: Extracellular Vesicle‐mimetic Nanovesiclesmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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RNAi delivery by exosome-mimetic nanovesicles – Implications for targeting c-Myc in cancer

Cited by 198 publications

References 40 publications

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

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RNAi delivery by exosome-mimetic nanovesicles – Implications for targeting c-Myc in cancer

Cited by 198 publications

References 40 publications

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

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BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells