Exosome-based tumor antigens–adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA

Morishita, Masaki; Takahashi, Yuki; Matsumoto, Akira; Nishikawa, Makiya; Takakura, Yoshinobu

doi:10.1016/j.biomaterials.2016.09.031

Cited by 292 publications

(209 citation statements)

References 53 publications

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“…4,[18][19][20] The intrinsic cell-targeting property of exosomes can be further enhanced by using genetic engineering techniques to introduce specific proteins to their surface, including ligands for receptors (Apo-A1) or antibodies directed against tumor biomarkers. 21,22 Alvarez-Erviti et al, for example, engineered exosomes produced by dendritic cells to express the neuron-specific rabies viral glycoprotein peptide, which binds to the acetylcholine receptor expressed on neuronal cells. These exosomes were shown to cross the BBB.…”

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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

221

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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mentioning

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

221

152

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“…Exosomes are engineered at the cellular level under natural conditions, but the successful modification of exosomes requires further exploration 21 . As compared with the cellular level endogenous method, which relies on biological approaches, exogenous methods, after production in cell culture, make exosome application more reliable when exosome source cells are not amenable to customized modification 12 .…”

Section: Introductionmentioning

confidence: 99%

Engineering exosomes as refined biological nanoplatforms for drug delivery

et al. 2017

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Exosomes, a subgroup of extracellular vesicles (EVs), have been recognized as important mediators of long distance intercellular communication and are involved in a diverse range of biological processes. Because of their ideal native structure and characteristics, exosomes are promising nanocarriers for clinical use. Exosomes are engineered at the cellular level under natural conditions, but successful exosome modification requires further exploration. The focus of this paper is to summarize passive and active loading approaches, as well as specific exosome modifications and examples of the delivery of therapeutic and imaging molecules. Examples of exosomes derived from a variety of biological origins are also provided. The biocompatible characteristics of exosomes, with suitable modifications, can increase the stability and efficacy of imaging probes and therapeutics while enhancing cellular uptake. Challenges in clinical translation of exosome-based platforms from different cell sources and the advantages of each are also reviewed and discussed.

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“…17,18 Genetic engineering transfects parent cells with encoded proteins of interest to generate exosomes with artificial receptors or other functional proteins. 17,19,20 This method is effective in introducing recombinant proteins on exosomal surfaces, however suffering from such intrinsic drawbacks as complicated manipulations and limited range of applicable proteins. Chemical modifications, on the other hand, employed hydrophobic interactions or covalent ligations to introduce chemical ligands or functional molecules onto exosomal surfaces.…”

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confidence: 99%

Molecular Recognition-Based DNA Nanoassemblies on the Surfaces of Nanosized Exosomes

et al. 2017

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Exosomes are membrane-enclosed extracellular vesicles derived from cells, carrying biomolecules that include proteins and nucleic acids for intercellular communication. Owning to their advantages of size, structure, stability, and biocompatibility, exosomes have been used widely as natural nanocarriers for intracellular delivery of theranostic agents. Meanwhile, surface modifications needed to endow exosomes with additional functionalities remain challenging by their small size and the complexity of their membrane surfaces. Current methods have used genetic engineering and chemical conjugation, but these strategies require complex manipulations and have only limited applications. Herein, we present an aptamer-based DNA nanoassemblies on exosome surfaces. This in situ assembly method is based on molecular recognition between DNA aptamers and their exosome surface markers, as well as DNA hybridization chain reaction initiated by an aptamer-chimeric trigger. It further demonstrated selective assembly on target cell-derived exosomes, but not exosomes derived from nontarget cells. The present work shows that DNA nanostructures can successfully be assembled on a nanosized organelle. This approach is useful for exosome modification and functionalization, which is expected to have broad biomedical and bioanalytical applications.

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Exosome-based tumor antigens–adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA

Cited by 292 publications

References 53 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

Engineering exosomes as refined biological nanoplatforms for drug delivery

Molecular Recognition-Based DNA Nanoassemblies on the Surfaces of Nanosized Exosomes

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