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Advanced Drug Delivery Reviews (v.65, #3)

Editorial Board (pp. ii).

Preface (pp. v).

Exosomes as nucleic acid nanocarriers by Jasper G. van den Boorn; Dassler Juliane Daßler; Christoph Coch; Martin Schlee; Gunther Hartmann (pp. 331-335).

Exosomes are nano-sized vesicles produced naturally by many cell types. They are specifically loaded with nucleic acid cargo, dependent on the exosome-producing cell and its homeostatic state. As natural intercellular shuttles of miRNA, exosomes influence an array of developmental, physiological and pathological processes in the recipient cell or tissue to which they can be selectively targeted by their tetraspanin surface-domains. By a review of current research, we illustrate here why exosomes are ideal nanocarriers for use in the targeted in vivo delivery of nucleic acids.Display Omitted

Keywords: Exosome; Extracellular vesicle; Nucleic acid; miRNA; Tetraspanin; ESCRT; RISC; miRISC; Targeted; In vivo; delivery

Mesenchymal stem cell: An efficient mass producer of exosomes for drug delivery by Ronne Wee Yeh Yeo; Ruenn Chai Lai; Bin Zhang; Soon Sim Tan; Yijun Yin; Bao Ju Teh; Sai Kiang Lim (pp. 336-341).

Advances in biomedical research have generated an unprecedented number of potential targets for therapeutic intervention to treat disease or delay disease progression. Unfortunately, many of these targets are not druggable as they are intracellular, present in many cell types, poorly soluble or rapidly inactivated. Although synthetic drug vehicles have successfully circumvented many of these problems, natural particulates such as exosomes that intrinsically possess many attributes of a drug delivery vehicle are highly attractive as potentially better alternatives. Of the cell types known to produce exosomes, the readily available proliferative, immunosuppressive and clinically tested human mesenchymal stem cell (MSC) is the most prolific producer. Its exosomes are therapeutic in animal model of disease and exhibit immunosuppressive activity. The quality and quantity of exosome production is not compromised by immortalization to create a permanent MSC cell line. Therefore, MSC is well suited for mass production of exosomes that are ideal for drug delivery.Display Omitted

Keywords: Mesenchymal stem cells; Exosomes; Drug delivery

Exosomes are endogenous nanoparticles that can deliver biological information between cells by Dongmei Sun; Xiaoying Zhuang; Shuangqin Zhang; Zhong-Bin Deng; William Grizzle; Donald Miller; Huang-Ge Zhang (pp. 342-347).

Exosomal particular size of 30–100nm matches the size criterion for nanoparticles, and opens up the possibility of using exosomes as a nanoparticle drug carrier. More importantly, exosomes released from different types of host cells have different biological effects and targeting specificities. Therefore, depending on the therapeutic goal, different types of exosomes can be combined with specific drugs and serve as carriers so that personalized medicine needs are met. In addition, exosomes do not appear to have cytotoxicity. Based on the perceived advantages of exosomes, they may well serve as a next generation drug delivery mechanism that combines nanoparticle size with a non-cytotoxic effect, target specificity, and a high drug carrying capacity, to make them useful in the treatment of a variety of diseases. This review will focus on exosomes as a biological nanoparticle drug carrier with emphasis on their immune-regulatory activities.Circulating exosomes with different targeting moieties are selectively transported into the tissue through the EPR effect (step1). The exosomes target a specific subset of cells that are either resident or newly arrived cells in the tissue (step2). Finally the biological effect of the exosomes on the targeted cells is determined by the encapsulated drugs and endogenous exosomal material.Display Omitted

Keywords: Exosome delivery vehicle; Nanoparticles; Immune regulation

Virus-modified exosomes for targeted RNA delivery; A new approach in nanomedicine by Danijela Koppers-Lalic; Marye M. Hogenboom; Jaap M. Middeldorp; D. Michiel Pegtel (pp. 348-356).

A major goal in biomedical research is to clinically reverse the cause of disease rather than treating the symptoms. Gene therapy has the potential to meet this goal and the discovery of RNA interference (RNAi) has lead to a new class of highly selective therapeutics. However, initial enthusiasm is reduced due to safety concerns associated with virus-based delivery vectors that are used for in vivo delivery.Viral vectors for siRNA delivery into target cells are used because of their high target specificity and delivery efficacy (endosomal escape). Recent discoveries suggest that a specialized form of nano-sized lipid vesicles called exosomes can incorporate and transport functional RNAs into target cells and may serve as an attractive alternative. Evidence is accumulating that most pluricellular organisms sustain exosome-based communications via inter-cellular exchange of mRNA and miRNAs between cells. We discovered that viruses have found ways to exploit this communication pathway and we argue here that adaptations of exosomes imposed by viruses maybe exploited for superior delivery of RNA in vivo. We discuss recent discoveries in exosome biogenesis their physical properties, targeting and delivery strategies and how the knowledge of exosome production in virus infected cells could propel their entry into clinical settings.Display Omitted

Keywords: Abbreviations; ABC; ATP-binding cassette; AGO; Argonaute; BACE1; β-site APP-cleaving enzyme 1; BBB; blood brain barrier; Dex; dendritic cell- derived exosome; EBV; Epstein–Barr virus; EE; early endosome; ESCRT; endosomal sorting complexes required for transport; HCC; hepatocellular carcinoma; ILV; intralumenal vesicles; imDC; immature dendritic cell; imDex; immature dendritic cell-derived exosome; LCL; latency type III lymphoblastoid B cell line; LE; late endosome; LMP1; latent membrane protein 1; mDex; mature dendritic cell-derived exosome; MDR1; multidrug resistance protein 1; miRNA; microRNA; mRNA; messenger RNA; MVB; multivesicular body; P-body; processing body; PEG; poly(ethylene glycol); piRNA; piwi-interacting RNA; RISC; RNA-induced silencing complex; RNAi; RNA interference; siRNA; small interference RNA; VLP; virus-like particles; VSV-G; G protein of vesicular stomatitis virusExosomes; MicroRNA; Genetic-transfer; Virus; Gene-therapy

Exosomes as nano-theranostic delivery platforms for gene therapy by Aaron Tan; Jayakumar Rajadas; Alexander M. Seifalian (pp. 357-367).

Exosomes are biological membrane vesicles measuring 30 to 100nm. They contain an abundance of small molecules like tetraspanins, receptors for targeting and adhesion, lipids, and RNA. They are secreted by most biological cells, and are involved in a plethora of physiological functions including, but not limited to, transport of genetic material, modulation of the immune system, and cell-to-cell communication. It has been further reported that exosomes utilize a mechanism similar to that of viruses for gaining entry into cells. Due to their viral-like transfection efficiency and inherent biological function, compelling evidence indicates that exosomes can be used as novel delivery platforms for gene therapy. Furthermore, RNA-containing exosomes derived from cells can serve as functional genetic biomarkers for diseases. This twin modality of therapeutic and diagnostic is termed theranostics in the emerging field of nanomedicine. Hence in this review, we seek to expound on the various facets of exosomes, highlighting their significance in and relevance to nano-theranostic platforms for gene therapy.Display Omitted

Keywords: Exosomes; Gene therapy; Theranostic; Drug delivery; Nanotechnology

The role of exosomes and microRNAs in senescence and aging by Dan Xu; Hidetoshi Tahara (pp. 368-375).

Senescence is viewed as a cellular counterpart to aging of tissues and organisms, characterized by an irreversible growth arrest and a combination of changes in cell morphology, function and behavior. microRNAs (miRNAs), the most studied small non-coding RNAs, play an important role in many biological processes by the regulation of gene expression. Recent evidence has shown that miRNAs are contained in exosomes that are tiny vesicles of endocytic origin and released by a variety of different cells as a means for cell-to-cell contact and information transfer. Exosomes and miRNAs have been found to participate in the complex networks of cellular senescence and contribute to aging. Here, we will give an overview on the involvement of secretory factors including exosomes and miRNA in the regulation of cellular senescence, demonstrating the potential role of exosomes and miRNAs in biological processes and signaling pathways of senescence and aging.Display Omitted

Keywords: Exosome; Aging; Senescence; MicroRNA; Tumor suppression; Age-associated disease

Exosomal tumor-suppressive microRNAs as novel cancer therapy by Nobuyoshi Kosaka; Fumitaka Takeshita; Yusuke Yoshioka; Keitaro Hagiwara; Takeshi Katsuda; Makiko Ono; Takahiro Ochiya (pp. 376-382).

MicroRNAs (miRNAs) act to fine-tune cellular responses in a variety of biological circumstances such as development, organogenesis, and homeostasis. The dysregulation of miRNA expression accelerates disease progression, including metabolic disease, immunological disease and cancer, through the gene network disorder. Therefore, understanding the miRNA maturation process may unravel the mechanisms of cancer malignancy; however, the life of miRNA has not been clarified. In this article, we summarize the recent findings regarding the novel forms of miRNA, especially secretory miRNAs, focusing on exosomal miRNAs. Recent research has revealed that exosomal miRNAs affect many aspects of physiological and pathological conditions, and may be useful as novel therapy. Here, we propose a method for the delivery of tumor-suppressive miRNAs to desired sites using exosomes, and we named this method “exocure”.Display Omitted

Keywords: Tumor-suppressive microRNA; Secretory microRNAs; Cell–cell communication; Tumor initiation; Exosomes; Small RNA therapy; Drug delivery system; Exosome; Microvesicle

Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models by Atsushi Suetsugu; Kimi Honma; Shigetoyo Saji; Hisataka Moriwaki; Takahiro Ochiya; Robert M. Hoffman (pp. 383-390).

Exosomes play an important role in cell-to-cell communication to promote tumor metastasis. In order to image the fate of cancer-cell-derived exosomes in orthotopic nude mouse models of breast cancer, we used green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes. Breast cancer cells transferred their own exosomes to other cancer cells and normal lung tissue cells in culture. In orthotopic nude-mouse models, breast cancer cells secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumor-associated cells as well as circulating in the blood of mice with breast cancer metastases. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in cancer metastasis.Display Omitted

Keywords: Exosome; GFP; RFP; Imaging; Breast cancer; Metastasis; CD63

Exosomes for targeted siRNA delivery across biological barriers by Samir EL Andaloussi; Samira Lakhal; Mager Imre Mäger; Matthew J.A. Wood (pp. 391-397).

Using oligonucleotide-based drugs to modulate gene expression has opened a new avenue for drug discovery. In particular small interfering RNAs (siRNAs) are being rapidly recognized as promising therapeutic tools, but their poor bioavailability limits the full realization of their clinical potential. In recent years, cumulating evidence has emerged for the role of membrane vesicles, secreted by most cells and found in all body fluids, as key mediators of information transmission between cells. Importantly, a sub-group of these termed exosomes, have recently been shown to contain various RNA species and to mediate their horizontal transfer to neighbouring- or distant recipient cells. Here, we provide a brief overview on membrane vesicles and their role in exchange of genetic information. We also describe how these natural carriers of genetic material can be harnessed to overcome the obstacle of poor delivery and allow efficient systemic delivery of exogenous siRNA across biological barriers such as the blood–brain barrier.Display Omitted

Keywords: Abbreviations; miRNA; microRNA; siRNA; small interfering RNA; RNAi; RNA interference; BBB; blood–brain barrier; MV; microvesicle; MVB; multivesicular body; MSC; mesenchymal stem cell; HSPC; hematopoietic stem progenitor cell; shRNA; small hairpin RNA; RISC; RNA-induced silencing complex dendritic cells (DC)Blood–brain barrier; Exosomes; Membrane vesicles; Microvesicles; Micro RNA; RNA interference; siRNA

Roles of exosomes and microvesicles in disease pathogenesis by Shin-ichiro Ohno; Akio Ishikawa; Masahiko Kuroda (pp. 398-401).

A variety of cells release membrane vesicles, such as exosomes and microvesicles (MVs), that are thought to play key roles in cell–cell communication, antigen presentation, and the spread of infectious agents throughout the body. There have been considerable efforts to use MVs as diagnostic or prognostic markers because their composition is reflective of minor physiological changes. Furthermore, recent studies demonstrate that MVs derived from infected cells and tumors contribute to disease pathogenesis. This review presents an overview of the potential roles of MVs with respect to clinical diagnosis and disease pathogenesis.Display Omitted

Keywords: Exosome; Microvesicle; Morphology; Immunology; Infectious disease; Neurological disease

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Advanced Drug Delivery Reviews (v.65, #3)