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In the s an unexpected gene-silencing phenomena in plants, the later called RNA interference RNAi , perplexed scientists. Following the proof of activity in mammalian cells, small interfering RNAs siRNAs have quickly crept into biomedical research as a new powerful tool for the potential treatment of different human diseases based on altered gene expression.

Lack of effective tumor-specific delivery systems remains an unmet clinical challenge for successful translation of innovative therapies, such as, therapeutic oligonucleotides. In the past decade, exosomes have been suggested to be ideal drug delivery systems with application in a broad range of pathologies including cancer, due to their organotropic properties.

Recent advances in siRNA delivery

Matteo, Pavia Italy,. Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Structurally, exosomes are composed of lipids, proteins, and also several types of RNAs which enable these vesicles to serve as important disease biomarkers. Moreover, exosomes have emerged as novel drug and gene delivery tools owing to their multiple advantages over conventional delivery systems.

Recently, increasing attention has been focused on exosomes for the delivery of drugs, including therapeutic recombinant proteins, to various target tissues.

Exosomes are also promising vehicles for the delivery of microRNAs and small interfering RNAs, which is usually hampered by rapid degradation of these RNAs, as well as inefficient tissue specificity of currently available delivery strategies. This review highlights the most recent accomplishments and trends in the use of exosomes for the delivery of drugs and therapeutic RNA molecules. Such nanocarriers are also present in body fluids such as blood, urine, amniotic effusions, malignant ascites, bronchoalveolar lavage fluid, synovial fluid, and breast milk.

Additionally, they have been found in the supernatants of different cell types grown in culture Mu et al. Such nanocarriers were first described 25 years ago in mature sheep reticulocytes involved in the externalization of the transferrin receptor Simpson et al. These vesicles can deliver biological information between cells through various surface adhesion proteins and ligands including tetraspanins, integrins, and CD11b and CD18 receptors Batrakova and Kim, They are formed from multivesicular bodies MVBs created by inward budding of late endosomes in the form of isolated intraluminal vesicles ILV and subsequently released to the extracellular milieu upon fusion with plasma membranes.

Sphingolipid ceramide and the phospholipid lysobisphosphatidic acid LBPA are considered important lipids in the process of ILV formation, which facilitates the inward transformation of the membrane. Moreover, plasma membrane proteins and cytoplasmic molecules are incorporated into the exosomes during its biogenesis, but this mechanism is not fully understood.

Initially, exosomes were thought to be a cellular mechanism to remove unwanted components. In this review, we have chosen to focus on different delivery approaches of noncoding RNAs and therapeutic drugs using exosomes.

However, in spite of major advances in the field of RNAi, only a few clinical trials have been performed. Investigations have revealed that naked siRNA has a natural affinity for gene silencing in the spleen, kidney, and liver. Viral delivery has inherent drawbacks, for example, it can result in the activation of complement or coagulant factors in the blood circulation. Moreover, viruses can be recognized by preexisting antibodies in the blood stream. There are also safety issues regarding dysregulation of gene expression in the desired tissue, which might lead to malignant transformation and several other complications, thus limiting the application of viral vectors in clinical practice Green et al.

Exosomes have some features that are common to liposomes including having a phospholipid bilayer and being composed of biocompatible substances Dang Xitong, It has been established that exosomes have benefits of a natural vehicle for transferring siRNAs with high target specificity and lack of immunologic reactions. This nanocarrier also has the properties of efficient uptake in host cells due to their unique composition of endogenously synthetized lipid, protein, and RNA, which is not found in other delivery systems Kooijmans et al.

In comparison with other existing gene therapy vehicles, repeated administration of exosomes did not activate the host immune response Hornung et al. Endogenous miRNAs can be encapsulated into exosomes to protect them from endonuclease degradation. This process leads to proliferation in neighboring normal cells. Exosomes loaded with an miRNA inhibitor are considered an effective carrier system compared with conventional transfection methods used to treat disease Wang et al. For therapeutic applications, such exosomes can be used both in either an unmodified, or engineered, form Mu et al.

Unmodified exosomes, which have been derived from various cell types, exhibit desirable therapeutic properties for various applications Zitvogel et al. Although exosomes may be generated from many cell types e. Furthermore, exosomes derived from endothelial cells provide an appropriate source of exosomes to deliver siRNAs to endothelial cells without any unnecessary components from nonendothelial origin.

Deriving exosomes from different types of cells may confer different compositions and functions Banizs et al. Electroporation represents just one broadly applicable method to introduce exogenous RNAs and other therapeutic molecules onto the surface of purified exosomes.

Therefore, the quality of exosomes prepared by electroporation depends on the conditions used, for example, buffers for resuspending the exosomes van der Meel et al. The electroporation protocol used for loading siRNA into exosomes has revealed conflicting results and has been reported to be hampered by the negative charge of siRNA.

Thus, siRNA complexes within a cationic liposome, followed by fusion with the exosome, may overcome many of the limitations associated with expulsion of the siRNA from the extracellular vesicle Wang et al. Another strategy to introduce miRNAs into exosomes is transient transfection using commercial transfection reagents Dang Xitong, ; Shtam et al.

Exosome display technology is another method to introduce exogenous siRNAs successfully into different kinds of human exosomes Wahlgren et al. To use exosomes as a potential therapeutic system, several issues need to be addressed. Therefore, several strategies have been developed to target exosomes to specific cellular receptors.

On the other hand, untagged exosomes deliver siRNAs to unintended tissues. Because there are many similarities between viruses and exosomes, exosomes may be modified by incorporating viral proteins, which may be exploited for specific targeting of the exosomes Sun et al.

Likewise, plasma exosomes, which were derived from the peripheral blood of healthy donors, were able to deliver siRNAs effectively into the target cells human blood mononuclear cells Wahlgren et al. The aim of this biotechnological approach has been to synthetize exosomes with a less complex structure and harness only crucial components of natural exosomes required for specific and efficient delivery of the exosomes to the target tissue.

Development of an immune response to PEGylated drugs can result in the accelerated clearance of nanocarriers. For example, PEGylated liposomes lose their circulating properties in the 2nd week after systemic administration in mice Hornung et al.

It has been suggested that exosomes may have stealth properties that blunt their clearance by the immune system Gibbings et al. One of the first examples of the application of exosomes in drug delivery was in targeted delivery of the chemotherapeutic drug doxorubicin to mice with solid tumors. Apart from efficacy, intravenous administration is less toxic compared with the fee drug due to the specific accumulation of exosomes in the tumor tissue.

Exosomes which are derived from mesenchymal stem cells are considered of therapeutic value for treating Alzheimer's disease AD. CDCs exosomes stimulated angiogenesis, induced cardiomyocyte proliferation, and reduced apoptosis in vitro. Exosomes derived from endothelial cells were suggested to be a promising strategy to combat atherosclerosis, since atherosclerosis is the fundamental cause of myocardial infarction and stroke. HUVEC exosomes were found to be enriched in multiple miRNAs resulting in controlled target gene expression and a reduction in atherosclerotic lesions of mouse aorta Mu et al.

Hypoxia induces an inflammatory response in the lung by activation of macrophages with a subsequent elevation of proinflammatory mediators that may cause later development of hypoxic pulmonary hypertension Lee et al.

MEX produced by umbilical cord mesenchymal stromal cells inhibit STAT3 signaling in isolated human pulmonary arterial endothelial cells, showing a direct effect of MEX on hypoxic vascular cells. Therefore, MEX exerts a protective effect on the lung and inhibits pulmonary hypertension by suppression of hyperproliferative pathways Lee et al. In this regard, exosomes have a capacity of delivering drugs directly to the tumor microenvironment.

Exosomes are selective candidates for use in vaccines for infections such as toxoplasmosis, diphtheria, tuberculosis, and atypical severe acute respiratory syndrome SARS. It has been reported that transfer of DCs pulsed with Toxoplasma gondii antigens TAg to healthy mice induced protection against a virulent strain of T. Infection with Mycobacterium tuberculosis stimulates macrophages to increase the release of exosomes and, it should be noted that microvesicles containing M.

Exosomes may be also candidates as vaccines for allergic diseases. Exosome like vesicles isolated from the bronchoalveolar lavage fluid of mice by respiratory exposure to the olive pollen allergen induced tolerance and protection against allergic sensitization in mice Prado et al. Exosomes are being considered as a therapeutic tool in moderating neovascularization. Activation of neovascularization can lead to an increased healing of wounds.

Exosomes may also be useful in the treatment of autoimmune diseases in animal models. Kim et al. Exosomes should be able to carry a sufficient amount of therapeutic cargo to qualify as drug delivery vehicles.

Exosomal formulations of catalase are a more versatile strategy to treat inflammatory and degenerative disorders like Parkinson's disease PD. Exosomes have been shown to be readily taken up by neuronal cells in vitro. To summarize, exosomes are naturally occurring nanovesicular structures that are secreted by almost all cell types in all body fluids. Being composed of not only lipid and protein, but also nucleic acids especially various RNAs , makes exosomes suitable as potential carriers for exogenous cargos, including RNAi and other therapeutic compounds Fig.

Furthermore, exosomes are capable of delivering exogenous therapeutic agents to a specific tissue. Schematic representation of the biogenesis of exosomes. Exosomes originate as endocytic vesicles through invagination of the cell membrane, which results in the formation of early exosomes and, subsequently, late exosome called MVBs. When MVBs fuse with the plasma membrane, they give rise to the release of exosomes into the extracellular space.

This process is involved in the creation of temporary RNAi. Exosomes are considered a promising strategy for effective and safe drug delivery to target cells. To accelerate the progress toward the routine use of exosomes for gene delivery, several issues need to be addressed.

For example, new and improved technology is critically needed to efficiently load therapeutic agents into exosomes. Additionally, obtaining highly purified exosomes in large quantities still requires further investigation. Exosomes: Nanoparticulate tools for RNA interference and drug delivery. J Cell Physiol. National Center for Biotechnology Information , U. Published online Jan Thomas P. Author information Article notes Copyright and License information Disclaimer. Amirhossein Sahebkar, Email: ri.

Corresponding author. Email: ri. Received Jan 3; Accepted Jan 5. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. This article has been cited by other articles in PMC. Abstract Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Open in a separate window. Figure 1.

Molecular Cancer , 13 DOI: Molecular Therapy , 19 2 , —

Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages

Voltage between 0. B Different amounts of MSC exosomes containing 0. The exosomal protein concentrations of 0. Exosomes, widely recognized natural nanovesicles, represent one of the recently discovered modes of intercellular communication due to their ability to transmit crucial cellular information that can be engineered to have robust delivery and targeting capacity. MiRp, one of the upregulated microRNAs miRNAs in many types of breast cancer, activates the canonical Wnt signaling pathway and transactivates the miR expression, and results in the hyperproliferation of cancer cells in vitro and mammary glands in vivo. In this study, we exploited the exosomes isolated from bone marrow-derived mesenchymal stem cells MSCs-Exo to deliver LNA locked nucleic acid -modified anti-miRp oligonucleotides to suppress the expression level of miRp and miR in 4T1 and TUBO breast cancer cell lines. We also evaluated in vivo distribution of the MSCs-Exo in tumor-bearing mice.

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Received 2 August Published 20 November Volume Pages — Review by Single anonymous peer review.

Exosomes: Nanoparticulate tools for RNA interference and drug delivery

Head and neck cancer HNC is one of the most common malignant neoplasms observed worldwide 1. Therefore, it is important to find novel treatment strategies for HNC. Uncontrolled invasion and metastasis contribute to this poor prognosis, and recent study results have suggested that epithelial-mesenchymal transition EMT serves an essential role in cancer cell metastasis, invasion, radiotherapy resistance, drug resistance, immune evasion and the cancer stem-cell phenotype 4 , 5. Previous studies have demonstrated that a number of critical biomarkers, including E-cadherin, N-cadherin and vimentin, are involved in EMT 5 , 6. The present study reported that that the expression levels of transient receptor potential polycystic 2 TRPP2, previously known as polycystin-2, PKD2 or PC2 , a nonselective cation channel encoded by the PKD2 gene, are markedly increased in laryngeal squamous cell carcinoma.

Exosomes are small, cell-secreted vesicles that transfer proteins and genetic information between cells. This intercellular transmission regulates many physiological and pathological processes. Therefore, exosomes have emerged as novel biomarkers for disease diagnosis and as nanocarriers for drug delivery. Here, we report an easy-to-adapt and highly versatile methodology to modulate exosome composition and conjugate exosomes for intracellular delivery.

Exosome-mimetic nanoplatforms for targeted cancer drug delivery

Matteo, Pavia Italy,. Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Structurally, exosomes are composed of lipids, proteins, and also several types of RNAs which enable these vesicles to serve as important disease biomarkers. Moreover, exosomes have emerged as novel drug and gene delivery tools owing to their multiple advantages over conventional delivery systems. Recently, increasing attention has been focused on exosomes for the delivery of drugs, including therapeutic recombinant proteins, to various target tissues.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over other artificial delivery tools.

Moreover, we analysed MOR expression levels in vitro and in vivo and morphine relapse in mice. Our study provides a brand new strategy for.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Exosomes, membranous nanovesicles, naturally carry bio-macromolecules and play pivotal roles in both physiological intercellular crosstalk and disease pathogenesis. Here, we showed that B cell-derived exosomes can function as vehicles to deliver exogenous miRNA mimic or inhibitor into hepatocytes or macrophages, respectively.

Сьюзан с опаской посмотрела на связанного шифровальщика. Стратмор сидел на диване, небрежно положив берет-ту на колени. Вернувшись к терминалу Хейла, Сьюзан приступила к линейному поиску. Четвертая попытка тоже не дала результата.

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