Protein VP2: Virion. Cytoplasm (Potential). Protein VP3: Virion. Cytoplasm (Potential). Protein VP1: Virion. Cytoplasm (Potential). Protein VP1-2A: Virion. Cytoplasm (Potential). Protein 2B: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum. Protein 2C: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum. May associate with membranes through a N- terminal amphipathic helix. Protein 3ABC: Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side (Potential). Mitochondrion outer membrane, ...
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
Exosomes are 30-100 nm microvesicles which contain complex cellular signals of RNA, protein and lipids. Because of this, exosomes are implicated as having limitless therapeutic potential for the treatment of cancer, pregnancy complications, infections, and autoimmune diseases. To date we know a considerable amount
Viruses enter host cells through interactions of viral ligands with cellular receptors. Viruses can also enter cells in a receptor-independent fashion.
Here we describe a method capable of identifying interactions between candidate trafficking proteins and a defined vesicle population in intact cells
Exosomes are small vesicles that are released from a variety of cells and are involved in cell-to-cell communication. In humans, exosomes are detected in the pl
Glioma microvesicles are abundantly shed into circulation, can be detected in the majority of clinical patients and are being explored as biomarkers for therapy...
When genes in the cell are turned on, the result is the production of gene copies called messenger RNAs, or mRNAs. The mRNAs are then used as templates to make proteins, the key molecules that enable the cell to function. But what happens to the excess mRNAs when they are no longer needed or the RNAs that have errors in them? They certainly cant remain active in the cell or serious problems would ensue.. A good analogy for the cells solution to this problem is the example of a common office and household machine. When we have sensitive documents around that are no longer needed, we use a handy specialized machine called a paper shredder to effectively eliminate the documents and the information they contain so it doesnt fall into the wrong hands. In the cell, a similar, but a far more complex machine has recently been characterized and described in a new publication in the journal Nature.1. When mRNAs are no longer needed in the cell, complex molecular machines called exosomes are recruited ...
Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix ...
Exosomes derived from cells and blood serum of patients with breast cancer, have been shown to initiate tumor growth in non-tumor-forming cells when Dicer and other proteins associated with the development of miRNAs are present," said Raghu Kalluri, M.D., Ph.D., chair of the department of cancer biology at MD Anderson. "These findings offer opportunities for the development of exosomes-based biomarkers and shed insight into the mechanisms of how cancer spreads." Exosomes are small vesicles consisting of DNA, RNA and proteins enclosed in a membranes made up of two lipid layers. They perform specialized functions such as coagulation, intercellular signaling and cell "waste management." They are shed into bodily fluids forming a source of disease-specific nucleic acids and proteins. Increasingly, exosomes are studied for their potential as both indicators of disease, and as a prospective new treatment approach.. All exosomes contain a cellular stew of smaller components including proteins, ...
Exosomes are lipid bound nanovesicles that are formed via the inward budding of the endosomal membrane, then released upon fusion of the endosomal limiting membrane with the plasma membrane. The majority of exosome studies involve the use of exosomes from bone marrow-derived dendritic cells or immortalised cell lines. This research project has focused on exosomes derived from primary B cells in response to T cell signalling, in particular via the CD40 and the interleukin-4 receptors. The fate of exosomes following their release is largely unknown. However as we have previously identified that B cell-derived exosomes are enriched in the antigen presenting molecules major histocompatibility complex class I (MHC-I), MHC-II and immunoglobulin, this may implicate B cell-derived exosomes in the transfer of antigen. We have sought to address the physiological role of primary B cell-derived exosomes and their interactions with other cells within secondary lymphoid tissue in vivo. We identified ...
Exosomes bud from the plasma membrane of T cells and may be the means of escape for newly formed retroviral particles, according to Booth et al. (page 923).. Exosomes are small vesicles that bud from the endosome membrane into its lumen. Following endosome fusion with the plasma membrane, the exosomes are released into the extracellular space.. Booth et al. found that the plasma membranes of cultured T cells have discrete domains enriched in proteins typically found in endosomes. The same sites were enriched for exosomal lipids, and small exosome-like vesicles were found just outside of these membrane sites, suggesting that exosomes can bud not only from endosomes but from the plasma membrane itself.. When T cells were engineered to express HIV Gag, which encodes the viral capsid proteins, the viral proteins were sorted to these membrane domains and budded from these sites in exosome-like vesicles.. The team thinks retroviruses have co-opted this endogenous cellular pathway for viral budding. ...
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Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. and irradiated recipient cells. We found an enhanced uptake of exosomes isolated Pyronaridine Tetraphosphate from both irradiated and non-irradiated cells by irradiated recipient cells compared to nonirradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate ...
Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. The role of exosomes in viral pathogenesis, especially human immunodeficiency virus type 1 [HIV-1] is beginning to unravel. Recent research reports suggest that exosomes from various sources play important but different roles in the pathogenesis of HIV-1. From these reports, it appears that the source of exosomes is the defining factor for the exosomal effect on HIV-1. In this review, we will describe how HIV-1 infection is modulated by exosomes and in turn how exosomes are targeted by HIV-1 factors. Finally, we will discuss potentially emerging
Excellgen Cre Recombinase Exosome Like Vesicles [EG-1020] - Description Cre Recombinase exosome-like vesicles are 20 to 50 nm lipid vesicles isolated from cultured mammalian cells. These vesicles encapsulate high concentration of NLS-Cre recombinase, but do not contain virus and nucleic acids (plasmid DNA, RNA etc). Addition of 10 ~ 50 µl of the vesicles to reporter cells (such as
Exosomes are small extracellular vesicles (EVs) secreted by many cell types in both normal and pathogenic circumstances. Because EVs, particularly exosomes, are known to transfer biologically active proteins, RNAs and lipids between cells, they have recently become the focus of intense interest as potential mediators of cell-cell communication, particularly in long-range and juxtacrine signaling events associated with adaptive immune function and progression of cancer. Among the EVs, exosomes appear particularly adapted for long-range delivery of cargoes between cells. Because of their association with disease states, the exciting potential for exosomes to serve as diagnostic biomarkers and as target-specific biomolecule delivery vehicles has stimulated a broad range of biomedical investigations to learn how exosomes are generated, what their cargoes are, and how they might be tailored for uptake by remote targets. Addressing these questions requires experimental models in which biochemically ...
In this interview, Dr. Pluchino discusses neuroimmunology-related applications of exosomes and how NPCs engage in cell-to-cell communication.
There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. As knowledge of the biogenesis, release and uptake of exosomes continues to evolve, and thus also has interest in these extracellular vesicles as potential tumor-targeted vehicles for cancer therapy. The ability to engineer exosome content and migratory itinerary holds tremendous promise. Studies to date have employed viral and non-viral methods to engineer the parent cells to secrete modified exosomes, or alternatively, to directly manipulate exosome content following secretion. The majority of studies have demonstrated promising results, with decreased tumor cell invasion, migration and proliferation, along with enhanced immune response, cell death, and sensitivity to chemotherapy observed. The studies outlined in
Exosomes are so-called extracellular vesicles, or small bubbles, released from cells, especially from stem cells. They act as shuttles for certain genetic information and proteins to other cells. They allow for cell-to-cell communication, transporting molecules that are important regulators of intracellular information between close and distant cells. They carry information from place to place with different functions and purposes telling cells how and when to react.
Polyclonal antibody for PCSK1 detection. Host: Rabbit.Size: 100μg/vial. Tested applications: IHC-P. Reactive species: Human. PCSK1 information: Molecular Weight: 84152 MW; Subcellular Localization: Cytoplasmic vesicle, secretory vesicle. Localized in the
Martin KR, Barua D, Kauffman AL, Westrate LM, Posner RG, Hlavacek WS, MacKeigan JP (2013) Computational model for autophagic vesicle dynamics in single cells. Autophagy 9, 74-92. PMID ...
Cambridge Healthtech Institutes Second Annual Exosomes and Microvesicles as Biomarkers and Diagnostics Conference, March 16-17, 2015 in Cambridge, MA Reporter: Aviva Lev-Ari, PhD, RN AGENDA http://www.extracellularbiomarkers.com/uploadedFiles/Extracellular_Biomarkers_Summit/Agenda/15/CFDX_Final.pdf#page=6 SOURCE From: Julia Boguslavsky |[email protected]| Date: Thu, 23 Oct 2014 13:45:00 -0400 To: |[email protected]| Subject: Exosomes as Biomarkers - Updates from Pfizer, Novartis, FDA, NIH, Harvard
Cells must be able to move molecules, digest particles, and secrete materials in order to survive. For many cellular functions, vesicles are used....
Page contains details about 1,2-dipalmitoyl-sn-glycero-phosphatidylcholine vesicles . It has composition images, properties, Characterization methods, synthesis, applications and reference articles : nano.nature.com
Kesimer M., Scull M., Brighton B., DeMaria G., Burns K., ONeal W., Pickles R.J., Sheehan J.K.. Airway mucus forms the structural basis of the local innate immune defense mechanism. It is an integrated, active, viscoelastic gel matrix evolved to protect the exposed lung from physical, chemical, and pathological erosion. Exosomes are biologically active vesicles secreted by different cell types including epithelial, hematopoietic, and some tumor cells. They are also present in some biological fluids such as serum, urine, breast milk, and bronchoalveolar lavage fluid. In this study, we demonstrate for the first time that exosome-like vesicles with antiviral properties are present in human tracheobronchial epithelial (HTBE) cell culture secretions. These vesicles have been isolated by differential centrifugation and are characterized further by mass spectrometry, flow cytometry, immunoblotting, electron microscopy, and light-scattering methods. HTBE vesicles exhibited characteristic exosomal size ...
Exosomes are 40-100 nm membrane vesicles of endocytic origin secreted by most cell types in vitro. Recent studies have shown that exosomes are also found in vivo in body fluids such as blood, urine, amniotic fluid, malignant ascites, bronchoalveolar lavage fluid, synovial fluid, and breast milk. While the biological function of exosomes is still unclear, they can mediate communication between cells, facilitating processes such as antigen presentation and in trans signaling to neighboring cells. Exosome-like vesicles identified in Drosophila (referred to as argosomes) may be potential vehicles for the spread of morphogens in epithelia. The advent of current MS-based proteomic technologies has contributed significantly to our understanding of the molecular composition of exosomes. In addition to a common set of membrane and cytosolic proteins, it is becoming increasingly apparent that exosomes harbor distinct subsets of proteins that may be linked to cell-type associated functions. The secretion ...
Exosomes are small secreted vesicles that have a diameter of ~50-200 nm. Exosomes are enriched for a specific subset of host-derived proteins, nucleic acids, lipids and carbohydrates, though they also incorporate most host cell molecules at baseline levels. Various models of exosome biogenesis have been proposed, but the field lacks the robust mechanistic studies that are needed to obtain a molecular understanding of vesicle secretion. To shed light on this process, our laboratory has taken a cargo-based approach in which we focus on the cis-acting signals that are necessary and sufficient for the budding of specific proteins. These studies have revealed that exosomal proteins are targeted to sites of vesicle budding by a combination of (1) high-order oligomerization and (2) binding to the plasma membrane. In addition, our work supports the hypothesis that the plasma membrane is a major site of exosome budding. Interestingly, HIV and other retroviruses have the same topology, size, and array of ...
Provided are compositions comprising naturally occurring vesicles, hybrid vesicles and vesicle populations, and methods using vesicle compositions to deliver therapeutic molecules for the treatment of cardiovascular disease.
Cell to Cell Communication: Exosomes Exosomes are extracellular vesicles that can contain proteins, lipids, nucleic acids and sugars, and play a key role
Exosomes are small extracellular vesicles of around 100nm of diameter produced by most cell types. These vesicles carry nucleic acids, proteins, lipids and other biomolecules and function as carriers of biological information in processes of extracellular communication. The content of exosomes is regulated by the external and internal microenvironment of the parent cell, but the intrinsic mechanisms of loading of molecules into exosomes is still not completely elucidated. In this study, by the use of next generation sequencing we have characterized in depth the RNA composition of healthy endothelial cells and exosomes and provided an accurate profile of the different coding and non-coding RNA species found per compartment ...
It has been assumed that exosomes are cellular trash bags for elimination of excess proteins, but many studies have shown that exosomes often exhibit certain specific markers, irrespective of the organ or cellular source. This suggests that certain proteins are transported to the exosomes with some degree of specificity. Additionally, distinct differences have been identified in the RNA and protein species present in exosomes, likely reflecting cellular and organ specificity. This second layer of complexity is dynamic and can change with the evolving status of the organ and cells within. Here, the pancreas is provided as an example, but this dynamism in exosomal contents presumably holds true for all organs. Therefore, exosome heterogeneity is a much more complex phenomenon than cellular heterogeneity and can be fleeting depending on stimuli and the functional status of the organ ...
Recent studies have reported significant roles of extracellular vesicle exosome in development and progression of various diseases including cancer metastasis. Therefore exosomes are considered as attractive targets for biomarkers and drug development. However, it remains difficult to isolate high-purity exosomes from biological fluids such as serum. EVSecond is a size exclusion chromatography open column optimized for effective purification of exosomes. Highly-purified exosomes can be easily collected from serum, plasma, or cell culture supernatant. ...
Exosomes are specialized, nanometer‐sized extracellular vesicles of endosomal origin actively secreted into the extracellular space by a variety of cells under normal and pathological conditions
Exosome-mediated switch of mRNAs and microRNAs is a novel mechanism of genetic alternate between cells. Exosomes are vesicles of endocytic origin launched by many cells. These vesicles can mediate ...
Exosomes are nanosized extracellular vesicles that allow communication between cells. They are seen to play a role in the progression of some cancers (e.g. prostate cancer, glioblastoma), as well as in resistance to cancer therapies. In fact, they modulate the immune response, explaining their role in either fighting the tumour or helping the tumour cells evade the immune system. ...
Urinary exosomes are becoming an crucial instrument in the review of kidney illness . In 4431-01-0addition to their potential to enrich proteins of fascination,
...   In a neuron, synaptic vesicles, also called neurotransmitter vesicles, store the various neurotransmitters that are released during
Enterobacteria-Secreted Particles Induce Production of Exosome-Like S1P-Containing Particles by Intestinal Epithelium to Drive Th17-Mediated Tumorigenesis
ABSTRACTSmall membranous vesicles are small closed fragments of membrane. They are released from multivesicular bodies (exosomes) or shed from the surface membrane (microvesicles). They contains various bioactive molecules and their molecular composition varies depending on their cellular origin. Sm
Exosomes are nanovesicles of endocytic origin that are about 30-100 nm in diameter, surrounded by a lipid bilayer membrane, and contain proteins, nucleic acids, and other molecules. Mammalian cells- a
A method for removing a gas from a site comprising placing cells having gas vesicles under conditions that induce the cells to float to a surface of an aqueous medium, harvesting the cells from the surface of the medium, lysing the cells, separating the gas vesicles from the lysed cells, crosslinking the gas vesicles with a crosslinking agent, loading a gas with a lowered partial pressure for the compound to be removed into the gas vesicles, and placing the gas vesicles such that the gas compound is removed from the site. Harvesting gas-vesicle-containing cells is achieved by placing the cells under conditions that induce the cells to rise to the surface of an aqueous medium-such as darkness, exponential growth stage, flocculation, or dissolved gas flotation-then collecting the cells from the surface of the medium. Gas vesicles are isolated by lysing the cells and separating the gas vesicles from the lysate. Once the gas vesicles are isolated, they can be modified, such as by crosslinking with
Exosomes are 30-150 nm extracellular vesicles that are endocytically released from cells. Exosomes were previously thought to simply exude unnecessary proteins from cells; however, more recent research has highlighted their importance in cell-to-cell communication by transporting biomolecules such as mRNA, microRNA, and protein through the circulatory system. Recipient cells may then take up these molecules, resulting in modulation of a wide variety of cellular functions. Notably, exosomes have been shown to play a role in antigen presentation and transportation of infectious materials from one cell to another.. Exosomes are secreted by most cell types and are found abundantly in many body fluids. As such, their potential as a source of diagnostic biomarkers is an area of intense interest. In fact, efforts are already underway to catalog exosomal proteomes. Advancements in proteomic tools, along with improvements in exosomal purification techniques, have contributed immensely to this effort. ...
To further assess the involvement of endogenous DRP-1 and DAPk in the membrane blebbing process during programmed cell death, we transfected 293 cells with low amounts of p55/TNFR1 DNA (up to 20% of the levels used in the previous experiments shown in Figs. 1 and 5) to achieve a mild response and slow the cell fragmentation process. The effects of dominant negative mutants of DAPk or DRP-1 on the morphological responses to p55/TNFR1 were assessed upon cotransfection. For inhibition of DRP-1, the previously described K42A mutant was used (Inbal et al., 2000), whereas for DAPk we used a substructure of the DAPk death domain fused to GFP (Raveh et al., 2000). Cell death morphology of GFP-positive cells was followed 24 h later, and the percentage of blebbed cells was scored. Transfection of p55/TNFR1 induced ∼20-45% blebbed cells at 24 h. Each of the mutants effectively reduced the fraction of these cells, thus proving their relevance to the process (Fig. 6 A). To further extend the scoring of ...
Multivesicular bodies (MVBs), and their intraluminal vesicles (ILVs), are involved in the sequestration of proteins destined for degradation in lysosomes. An alternative fate of MVBs is their exocytic fusion with the plasma membrane leading to the release of the 50-90 nm ILVs into the extracellular milieu. The secreted ILVs are then called exosomes." [1].. Exosomes also express specific cell-surface proteins including integrins and cell adhesion molecules, so they have the means to bind selectively to, and be taken up by, specific recipient cell types [1-3].. As such, secretory exosomes can be distinguished from cell debris released from dead or dying cells, and from microvesicles, which are larger (up to 1 micron), denser, and occur via pinching-off from the plasma membrane; microvesicles may contain mitochondria, lysosomes and even DNA. Note that some authors use the term "microvesicle" generically to include secretory exosomes and even miscellaneous intracellular vesicles resembling synaptic ...
van der Pol E, Coumans FAW, Grootemaat AE, Gardiner C, Sargent IL, Harrison P, Sturk A, van Leeuwen TG, Nieuwland R. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost 2014; 12: 1182-92.. Sarah E. Headland, Hefin R. Jones, Adelina S. V. DSa, Mauro Perretti & Lucy V. Norling Cutting-Edge Analysis of Extracellular Microparticles using ImageStreamX Imaging Flow Cytometry. Nature Scientific Reports 4 : 5237 DOI: 10.1038 June 10 2014.. Erdbrügger U, Rudy CK, E Etter M, Dryden KA, Yeager M, Klibanov AL, Lannigan J. Imaging flow cytometry elucidates limitations of microparticle analysis by conventional flow cytometry. Cytometry A. 2014 Sep;85(9):756-70. doi: 10.1002/cyto.a.22494. Epub 2014 Jun 5.. ...
During human pregnancy, placenta-associated serum exosomes are involved in cell-cell communication between the placenta and peripheral vascular endothelial cells (29). The present study isolated serum exosomes with PLAP-positive expression by PEG precipitation and ultracentrifugation with a sucrose gradient, which led to the isolation of placenta-associated exosomes with high purity and yield. The present study demonstrated that placenta-associated serum exosomes from patients with PE reduced NO production and eNOS expression in endothelial cells; this effect may be partly due to the increased expression of miR-155 in placenta-associated serum exosomes.. Previous studies have accumulated evidence regarding the physiological function of serum exosomal miRNAs. Squadrito et al demonstrated that serum/plasma exosomal miR-122 and miR-155 are predo minantly associated with inflammatory liver injury (30). Another study indicated that serum exosomal miR-21 is positively correlated with tumor progression ...
Supplementary MaterialsSupplement 1. of exosomes in individual vitreous. The concentrations of vitreous vesicles in vitrectomy individuals, postmortem donors, and mice were 1.3, 35, and 9 billion/mL, respectively. Conclusions Overall, these data strongly suggest that information-rich exosomes are a major constituent of the vitreous. The large quantity of these vesicles and the presence of retinal proteins imply a dynamic interaction between the XL184 free base price vitreous and retina. Long term studies will be required to determine the cellular source of vitreal exosomes as well as to assess the potential part of these vesicles in retinal disease and treatment. Translational Relevance The recognition of vitreous exosomes lays the groundwork for any transformed understanding of pathophysiology and treatment mechanisms in retinal disease, XL184 free base price and further validates the use of vitreous like a proximal biofluid of the retina. for 12 moments. Mass Spectrometry Electrospray ...
The researchers determined that the protective effects of exosomes are mediated by microRNA, molecules that interfere with or silence gene expression. Further research is needed to understand more about the specific contents of the exosomes, said Stanislav Tomarev, Ph.D., a principal investigator at NEI and the studys coauthor.. "We need to know which particular microRNA - there are more than 2000 different microRNA molecules - are delivered into the retinal ganglion cells and what proteins or signaling pathways are being targeted upon arrival," said Tomarev. "We also need to attempt to target exosomes to specific sets of neurons and other cell types or groups of cells.". Finally, the most optimal exosome approach needs to be identified, Tomarev added. It may be that the best approach would be to combine exosomes with additional therapies. From a treatment feasibility standpoint, a lot will depend on how frequently exosomes need to be administered to achieve a therapeutic effect.. ...
RNA interference (RNAi) therapeutics (siRNA, miRNA, etc.) represent an emerging medicinal remedy for a variety of ailments. However, their low serum stability and low cellular uptake signi cantly restrict their clinical applications. Exosomes are biologically derived nanodimensional vesicle ranging from a few nanometers to a hundred. In the last few years, several reports have been published demonstrating the emerging applications of these exogenous membrane vesicles, particularly in carrying different RNAi ther- apeutics to adjacent or distant targeted cells. In this report, we explored the numerous aspects of exosomes from structure to clinical implications with special emphasis on their application in delivering RNAi-based therapeutics. siRNA and miRNA have attracted great interest in recent years due to their speci c applica- tion in treating many complex diseases including cancer. We highlight strategies to obviate the challenges of their low bioavailability for gene therapy ...