Exosome nanocarriers

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Exosome nanocarriers: a natural, novel, and perspective approach in drug delivery system

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Jasvinder Singh Bhatti1, Rajesh Vijayvergiya2, Bhupinder Singh3 and Gurjit Kaur Bhatti3,4 1

Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh, India 2Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India 3 UGC Centre of Excellence in Nano Applications, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India 4University Institute of Pharmacy Sciences, Chandigarh University, Mohali, Punjab, India

ABBREVIATIONS miRNA ILVs MVE EVs RLPs MHC mRNA ESCRT IL DCs APCs CD NF-κB TNF-α PD AD DNA RNA T2DM BBB siRNA EFGR

micro RNA intraluminal vesicles multivesicular endosomes extracellular vesicles retrovirus-like particles major histocompatibility molecules messenger RNA endosomal sorting complexes required for transport interleukins dendritic cells antigen presenting cells cluster of differentiation nuclear factor kappa-light-chain-enhancer of activated B-cells tumor necrosis factor-α Parkinson’s disease Alzheimer’s disease deoxyribonucleic acid ribonucleic acid type 2 diabetes mellitus blood brain barrier small interfering ribonucleic acid epidermal growth factor receptor

Nanoarchitectonics in Biomedicine. DOI: https://doi.org/10.1016/B978-0-12-816200-2.00008-6 © 2019 Elsevier Inc. All rights reserved.

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7.1 INTRODUCTION The extracellular vesicles (EVs) are naturally present in many biological fluidsand are classified by their functionality, morphological properties, and origin/biogenesis (Street et al., 2012; Bobrie et al., 2011; Buzas et al., 2014). EVs are mainly classified into four broad types according to their biogenesis as exosomes, microvesicles (MVs), apoptotic bodies, and retrovirus-like particles (RLPs) (EL Andaloussi et al., 2013; van der Pol et al., 2012). The origin of MVs, apoptotic bodies, and RLPs occurs by direct budding from the plasma membrane. However, exosomes originate by the process of exocytosis of the multivesicular bodies (MVBs). Recent studies demonstrated that MVs are bigger than exosomes (Akers et al., 2013). MVs bear different nucleic acids and proteins such as actin, tubulin, β1 integrins, and vesicle-associated membrane protein 3 (Buzas et al., 2014). The main feature of all these vesicles is the endosomal biogenesis as intraluminal vesicles (ILVs) within multivesicular endosomes (MVEs), which is different from the origin of other vesicles shedding from the plasma membrane (Kalra et al., 2012; Raposo and Stoorvogel, 2013). Inward invagination of the membrane results in the continuous addition of vesicles in the lumen of MVE into the extracellular space and was first observed in rat reticulocytes (Harding et al., 2013). It has been recognized that after the cells undergo apoptosis they form small vesicles known as apoptotic bodies (Emanueli et al., 2015). In fact, these small vesicles were identified as debris and considered as a means of wrapping the leftovers of the dead cells following an approach that there should not be any collateral damage to the cells in surrounding area. On the other hand, evidence has already materialized the fact that the EVs, in the size range of 30 nm to 1 μm, are not released during cell death but necessarily have their own a biological function (Emanueli et al., 2015). Exosomes are tiny-sized (ranging in 30 100 nm in diameter) membranous vesicles secreted by a variety of cell types in the body through the endosomal pathway. They were first reported in 1981 as exfoliation from monolayer cultures and subsequently demonstrated by Johnstone and his team (Johnstone et al., 1991; Trams et al., 1981). They are known to be associated with diverse pathological conditions and represent a variety of functions like delivering biomolecules and genetic material to recipient cells. Exosomes are enriched with a bundle of specific molecules which are different from proteins normally located in the plasma membrane including tetraspanins (CD9, CD63, CD81, and CD82), heat-shock proteins (HSP60, HSP70, HSPA5, CCT2, and HSP90), major histocompatibility molecules (MHC-I and MHC-II), cytoskeleton proteins (actin, tubulin, cofilin, myosin, vimentin, fibronectin, advillin, talin, CAP1, keratins, and meosin), microRNA (miRNA), messenger RNA (mRNA), Annexins (I, II, IV, V, VI, VII, and X1), apoptotic bodies, and many more (Akers et al., 2013; Keller et al., 2006; Hristov et al., 2004).

7.1 Introduction

Exosomes also contain a domain of lipids including cholesterol, sphingomyelin, ceramide, and ganglioside called membrane rafts (Fig. 7.1). There is another class of cytosolic proteins found in the exosomes includes Rabs, a family of GTPases involved in vesicular transport and protein complexes that regulate membrane fusion and docking. About 40 Rab proteins have been identified in the exosomes RAB27A, RAB27B, RAB11, and RAB35 (Bobrie et al., 2011; Ostrowski et al., 2010). Exosomes are special in their way as they possess particular cell surface markers as a legacy from the cell of their origin. These cell surface

FIGURE 7.1 Structural components of the exosome. Exosomes are composed of a bundle of specific molecules including tetraspanins (CD9, CD63, CD81, CD82), HSPs (HSP60, HSP70, HSPA5, CCT2, and HSP90), MHCs (MHC-I and -II), cytoskeleton proteins (actin, tubulin, cofilin, myosin, vimentin, fibronectin, advillin, talin, CAP1, keratins, meosin), microRNA and mRNA, Annexins I, II, IV, V, VI, VII and X1, and apoptotic bodies. Exosomes also have a domain of lipids including cholesterol, sphingomyelin, ceramide, and ganglioside called membrane rafts. There is another class of cytosolic proteins found in exosomes including Rabs, a family of GTPases involved in vesicular transport and protein complexes that regulate membrane fusion and docking. HSP, Heat-shock protein; MHC, major histocompatibility molecule; mRNA, messenger RNA.

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markers provide the exosomes the means of interaction with neighboring and distant cells (Skokos et al., 2003). Possession of these qualities has made exosomes a valuable therapeutic tool with inherent qualities in the biomedicine research area for targeted drug delivery to counter deadly diseases. In addition to lipids, proteins, and mRNA, exosomes also transfer miRNA to recipient cells which can alter the pathologic genetic expression (Valadi et al., 2007). It has been a long journey to come to understand the actual morphology and functions of exosomes concerning the dynamic role in intercellular communication by transporting a broad range of bioactive molecules between different cells and tissues (Tkach and Thery, 2016). This function allows exosomes to regulate many physiological activities, including the immune response.

7.2 EXOSOME BIOGENESIS, RELEASE, AND UPTAKE The secretion of exosomes in the cells occurs by fusion of the MVB and the cell membrane’s most vibrant compartments which are actively involved in internalization of extracellular ligands, post membranous invagination, and release of various kinds of endocytic vesicles. During these processes, some membrane proteins get transferred to these vesicles. Exosomes are formed by the inward budding of the endocytic vesicles and contain cytoplasmic components. Continuous formation of exosomes leads to the development of MVBs. The membrane of MVBs is semipermeable and ensures that cargoes are selectively loaded into the exosomes. Exosomes can have similar kinds of membrane constituents even if they have originated from different types of cells (Bartel, 2004). Exosomes keep the basic topology of the membrane intact; phosphatidylserine on the exterior while the cytosolic side of lipid bilayer remains inside. This arrangement causes the isolation of signal domains of the membrane receptors, thereby restricting their functionality of dampening the signal transduction. On the other hand, the luminal part remains exposed. Fig. 7.2 shows the exosome biogenesis and release of exosomes from the endocytic compartment of live cells. The preliminary steps involved in sorting the proteins undergoing endocytosis are the inward budding processes on the cell surface, which can be clathrindependent and independent ways. The endocytotic vesicles are transferred to endosomes which have an internal acidic environment. The acidic pH gets reduced by some modification in the protein composition in the late endosomes which shed into the endosomal lumen to form MVBs and further leads to the formation of ILVs. MVBs are abundant in cholesterol which can have dire consequences for cell survival, so they get fused with the plasma membrane and release exosomes but MVBs with a low amount of cholesterol fuse with the lysosomes and are involved in proteolysis. There are mainly two mechanisms involved in the formation of exosomes; ESCRT (endosomal sorting complexes required for transport) dependent (which comprises four proteins O, I, II, III, and lipid-dependent)

7.2 Exosome Biogenesis, Release, and Uptake

FIGURE 7.2 Mechanism of exosome biogenesis. Early endosomes arose through clathrin-mediated endocytosis at the plasma membrane and converted into late endosomes by changing the protein content and acidification. Then, MVBs are derived from late endosomes budding into their endosomal lumen, and cholesterol-rich MVBs interact with the plasma membrane to secrete exosomes. Exosomes are formed by invagination MVBs that fuse with the plasma membrane. MVB, Multivesicular body.

and ESCRT independent. ESCRT-O separates ubiquitinated proteins, I and II complexes help in budding, and III completes the process and leads to the formation of ILVs in the MVBs rich population. Exosomes firstly originate as ILVs then get matured to MVEs (Huotari and Helenius, 2011; Hanson and Cashikar, 2012). Tetraspanins such as CD81, CD9, and CD63 play a fundamental role in the composition of ESCRT-independent loading into exosomes by organizing the membrane into tetraspanin-enriched domains. The ESCRT complex mechanism, both dependent and independent, for packing of protein cargo into exosomes is a sign of the existence of different MVB and exosome populations. Different types of cancerous cells secrete different types of exosomes which vary in morphology and miRNA composition (Palma et al., 2012; Penfornis et al., 2016), but some secret exosomes which get differentiated by surface antigens having different protein content with various functions. The exosomes released from apical and basolateral cell membranes may have the heterogeneous population of vesicles, but the existence of controlled and specialized mechanisms control the selective, specific sorting of protein and miRNA cargo into these vesicles. While numerous researchers explained the biogenesis of exosomes, most of these mechanisms are still unclear.

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7.3 EXOSOMES IN BIOLOGICAL FLUIDS Exosomes play a vital role in intercellular communication or as disease biomarkers. An attribute that is independently measured and evaluated as an indicator of a biologic, pathogenic process or pharmacologic response to a therapeutic intervention is referred to a biomarker (Biomarkers Definitions Working, 2001). Indeed, exosomes are secreted by a variety of biological fluids and cells including extracellular fluids, amniotic fluid, cultured cells, cerebrospinal fluid, synovial fluid, bronchoalveolar lavage fluid, blood, breast milk, saliva, urine, semen, bile, and nasal mucus (Johnstone et al., 1987; Michael et al., 2010; Admyre et al., 2007; Keller et al., 2011; Vella et al., 2008; Skriner et al., 2006). Particularly, exosomes released from serum or plasma fluids are more accurate for the development of biomarkers. These blood-based biomarkers can predict patients’ biochemical parameters more accurately and further predict the response to therapeutic intervention helping in earlier diagnosis and inhibiting the development of severe complications. Exosomes from various tissues of the body released into the blood stream can be distributed to distance tissues, and in the specified target tissue they regulate gene transcription, posttranslational modification, and signal transduction. Assorted cellular cargoes released by exosomes become a source of blood-based biomarkers and these biomarkers point toward the pathophysiological mechanisms which could be extremely useful in identifying cardiovascular complications associated with diabetes. That is the reason that plasma- and serum-derived exosomes act as a specific molecular marker for various tissues and determine the pathophysiological condition if any. Exosomes released from the other fluids like milk, saliva, and cerebrospinal fluid can be tissue specific. Although the exosomes exist in almost every biological body fluid, their existence in the serum and plasma is known to be of particular importance and can be exploited as biomarkers. The most important step in the isolation of exosomes and their development into biomarkers is to make sure of the exosomes’ enrichment in the extracellular milieu, which is quite complicated. Plasma and serum are the biological fluids which represent the extracellular environment of almost every organ, thereby; the efficacy of exosomes is entirely dependent on the matrix of the sample. The procedure of isolation of exosomes from biological fluids is a tedious method. Therefore many methods for isolation of exosomes have been standardized but a single optimized method has not been established till date. Out of available methods, the most widely used is differential centrifugation. Different sizes of vesicles get separated after the subsequent rounds of centrifugation, that is, large vesicles (2000 g, 10 minutes), MVs greater than 150 nm (10,000 g, 30 minutes), and exosomes (100,000 g, 70 minutes) (Schulte et al., 2016). However, this method also requires further optimization for the duration of each centrifugation according to the rotor type used. Sedimentation efficiency and density of EVs of varying sizes are dependent on the sedimentation path length and the duration of centrifugation,

7.4 Role of Exosomes in the Pathogenesis

which should be calculated for every individual rotor to minimize the presence of nonexosomal vesicles and MVs (Livshits et al., 2016; Cocucci et al., 2007; Eken et al., 2008). The size-based characterization of the isolated exosomes is done with at least three exosomal markers, for example, tetraspanins, TSG101, and Alix. Nonexosomal markers including Grp94, GM130, and cytochrome C are used for confirming the absence/low levels of contamination (Lotvall et al., 2014). Moreover, morphological characters are also analyzed by electron microscopy. During ultracentrifugation, the membrane of the exosomes may get disrupted and lead to the formation of aggregates of different shapes and sizes which may pose difficulties in the interpretation of the biomarkers (Linares et al., 2015). Size exclusion chromatography is also one of the methods used to isolate exosomes by size and chances of getting vesicles of regular and homogeneous shape with negligible damage are more when using this method. Currently, standard kits are commercially available in the market to isolate exosomes from the lesser volume of biological fluids.

7.4 ROLE OF EXOSOMES IN THE PATHOGENESIS, DIAGNOSTICS, AND THERAPEUTICS Exosomes display a wide variety of functions in the cell including cell cell communication, diagnostic markers, and potential roles in therapeutics. Furthermore, recent studies demonstrated the possible role of exosomes as a biomarker for early diagnosis of diseases (Simpson et al., 2009; Pisitkun et al., 2006). In the past few years more attention has been focused on the role of exosomes in the pathophysiology of a variety of diseases including cancer, metabolic disorders, cardiovascular diseases, immune diseases, and neurodegenerative diseases.

7.4.1 EXOSOMES IN INFLAMMATORY DISEASES Exosomes are known to play a vital role in treating various inflammatory reactions and autoimmune diseases as potential therapeutic agents. On the one hand, exosomes released from infected cells demonstrate a variety of functions. Further, the exosomes released from pathogen-stimulated brain cells have miRNAs which could interfere with the gene expression of various other cells (Gupta and Pulliam, 2014). In asthmatic patients, the release of exosomes from the bronchial epithelial cells in the lungs is enhanced and might be responsible for the increase in intercellular signaling. Exosomes released from the epithelial cells treated with interleukins 13 (IL-13) stimulate the inflammation along with the cell proliferation, but some specific drugs that result in the inhibition of exosomes production can lead to diminishing the inflammation (Kulshreshtha et al., 2013). Exosomes from Mycobacterium tuberculosis infected macrophages have mycobacteria-derived antigens and cause the induction of inflammatory immune

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responses while inhibiting IFN-γ dependent activation of macrophages (Bhatnagar et al., 2007; Singh et al., 2011). In a similar way, exosomes released from Mycobacterium smegmatis or Mycobacterium avium infected macrophages will have great Hsp70 expression; however, the stimulation of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway helps in the production of high levels of tumor necrosis factor-α (TNF-α). Exosomes with Hsp70 expression can produce a proinflammatory response with the release of TNF-κB by macrophages and promotion of NK cell activity (Gastpar et al., 2005). Curcumin loaded exosomes have been used to activate myeloid cells, which are involved in control and/or development of autoimmune diseases associated with inflammation. These hydrophobic compounds loaded onto exosomes were readily internalized by mouse lymphoma cells (EL-4) (Sun et al., 2010). Exosomal curcumin helps in decreasing the number of CD11b 1 Gr-1 1 cells which are responsible for causing acute lung inflammation by increasing the solubility, stability, and bioavailability of curcumin after the encapsulation into the lipid bilayer of exosomes. Nevertheless, it becomes easier to deliver the encapsulated curcumin to the brain through intranasal administration. Recently, an in vivo study explained the efficacy and effectiveness of curcumin-loaded exosomes in the treatment of neuroinflammatory diseases (Zhuang et al., 2011). Exosomes released from the dendritic cells (DCs) have received much attention lately. Pretreated DCs with adenovirus express IL-10 and exhibiting an antiinflammatory response. Conversely, exosomes released from DCs with the expression of IL-10 were established as immunosuppressive and help in suppressing T-cell proliferation and the delayed type of hypersensitivity response in collagen-induced arthritis (Kim et al., 2005). Exosomes released from the DCs produced much improved therapeutic results in comparison to the parental DCs (Kim et al., 2007). Intravenous administration of 10 μg of TGF-β/exosomes may have prevented weight loss with reduced intestinal bleeding in mice with inflammatory bowled disease. The suppression of the symptoms might be due to stable TGF-β in exosomes following intravenous administration and, hence, increased activity (Cai et al., 2012b). These results indicated that exosomes were effective nanocarriers for the delivery of biological agents for treating inflammatory diseases. Previous in vitro studies demonstrated that the exosomes released from the Epstein Barr virus cause some changes in the B-cells, and present MHC class II molecules lying on the membrane to CD4 1 T-cells (Raposo et al., 1996; Admyre et al., 2006; Liu et al., 2006). Other reports demonstrated that exosomes released from DCs stimulate CD8 1 T-cell-dependent antitumor immune response in vivo experiments (Zitvogel et al., 1998). Some research reports indicate that exosomes released from the antigen presenting cells (APCs) have the ability to stimulate the T-cells, but other reports suggest that APCs need exosomes beforehand in the case of T-cell stimulation (Admyre et al., 2006). However, it was revealed that MHC molecules fostered with exosomes have the capability of coming together with the T-cell receptors and can initiate

7.4 Role of Exosomes in the Pathogenesis

the production of CD4 1 and CD8 1 cells. Some reports came forward with the fact that MHC peptides loaded with exosomes, when transferred to DC, can stimulate naı¨ve T-cells (Thery et al., 2002a). T-cell stimulation by means of exosomes is recognized to be dependent on the physiological conditions of the origin cell, but matured DC-derived exosomes trigger T-cell activation in a much more efficient manner compared to immature ones (Segura et al., 2005; Montecalvo et al., 2008). Exosomes also carry antigenic properties so they can be degraded in that way too. Exosomes derived from pathogen-infected cells need to carry some specific antigenic properties which may be inherited from that particular pathogen and can induce CD4 1 and CD8 1 T-cell proliferation (Montecalvo et al., 2008; Bhatnagar and Schorey, 2007). Previous studies have revealed that exosomes secreted from cancerous cells release certain cytokines into the microenvironment which are attributed with triggering the immune response against tumorigenic tissue (Wolfers et al., 2001; Dai et al., 2006). On the contrary, exosomes derived from tumor tissue demonstrate exactly the opposite immune response in a manner of bearing different immunosuppressive molecules. This happens because of either decline in CD4 1 , CD8 1 , and natural killer cell stimulation or amplification in the differentiation of the immunosuppressive cells (Bobrie et al., 2011). Injecting exosomes derived from tumor cells supported metastasis by decreasing natural killer cells activation, but increase the differentiation of myeloid cells and lead to the development of melanoma and carcinoma (Liu et al., 2006). Till date, there is no relevant explanation for these controversial results reported by different scientists, but it could be speculated to be due to the heterogeneous population of exosomes.

7.4.2 EXOSOMES IN CANCER Cancer is the leading cause of mortality worldwide. Current treatment methods include surgery, chemotherapy, and radiation which further raises toxicity concerns. Since these methods are unable to cure metastasis of the cancerous cells there is a great need to develop more effective and less toxic therapies. Immunotherapy is a much-explored way of treatment for many types of cancers. Antibodies have exhibited a clinical accomplishment for cancer immunotherapy as well (Scott et al., 2012). Recent research reports show the potential role of exosomes in cancer treatment as well as diagnosis and prognosis (Salido-Guadarrama et al., 2014; Mahaweni et al., 2013; Chaudhuri et al., 2011; Gross et al., 2012; Lai et al., 2013; Zhang et al., 2016; Chaput et al., 2003; Basu and Ludlow, 2016; Viaud et al., 2008; Cho et al., 2012; Soekmadji et al., 2013). The proteins and RNA content from tumor-derived exosomes are involved in disseminating malignancy to recipient cells. This may provide diagnostic information and aid in therapeutic selection for cancer patients. The most important fact about exosomes is their ability to stimulate the immune response that can be exploited for the development of cancer vaccines (Tan et al., 2010).

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Many studies have demonstrated the therapeutic potential of DC-derived exosomes in cancer physiology (Chaput et al., 2006; Munich et al., 2012; Pitt et al., 2014, 2016; Viaud et al., 2010; Delcayre et al., 2005; Romagnoli et al., 2014; Zitvogel et al., 1999). Currently, much attention is being given toward exosomes and how to use them as gene delivery systems to specifically target tumor cells (Shtam et al., 2013). Exosomes also have the ability to act as a shuttle for antigen presentation and could be used as cancer vaccines in the near future (Natasha et al., 2014). Exosomes released by immune-suppressive DCs can suppress inflammatory responses and this potential could be used in treating autoimmune diseases (Kim et al., 2005; Yang and Robbins, 2012). Exosomes released from DCs carrying tumor-specific peptides can provoke cytotoxic T lymphocytes to respond and, consequently, inhibit tumor growth (Wolfers et al., 2001). Exosomes released from APCs contain tumor antigens which have been shown to encourage CD4 1 and CD8 1 T-cells and finally results in suppressing tumor growth (Zitvogel et al., 1998). Exosomes can initiate apoptosis by the activation of PTEN and GSK-3β that leads to the inactivation of PI3K/AKT which, in turn, plays a major role in tumor growth (Ristorcelli et al., 2008). Cancer cells are efficient in modulating the normal functioning of immune cells of the body’s defense mechanism and become malignant. The macrophages uptake of exosomes released by cancerous cells leads to the activation of NF-κB and, as a result, there are upregulation inflammatory cytokines (IL-6, TNF-α, GCSF, and CCL2) in the macrophages. Toll-like receptor 2 expressions on the surface of macrophages of these exosomes regulates the immune regulation which is mediated by the presence of palmitoylated protein ligands on the surface of tumor-derived exosomes (Chow et al., 2014).

7.4.3 EXOSOMES IN NEURODEGENERATIVE DISEASES Exosomes are involved in a variety of neurological disorders including Parkinson’s disease (PD) and Alzheimer’s disease (AD) (Haney et al., 2015; Wu et al., 2016; Russo et al., 2012; Rajendran et al., 2006; Malm et al., 2016; Vella et al., 2016). They are released by numerous cell types, whether normal or pathogenic, into the extracellular environment. Particularly, exosomes released by tumor tissues initiate the metastasis and highlight the fact that exosomes have the ability to spread diseases within the body (Costa-Silva et al., 2015; Hoshino et al., 2015). This ability of exosomes to spread the diseases is considered to be responsible for neurodegenerative disorders. The cause of neurodegenerative diseases is mainly the deposition of certain misfolded and aggregated forms of protein molecules in brain tissue. These misfolded proteins further spread to different parts of the body as the disease progresses (Braak et al., 2003). Biochemical and molecular analysis of cerebral spinal fluid and blood of patients suffering from several neurodegenerative diseases illustrated the presence of many misfolded and aggregated proteins which are carried by exosomes. Exosomes contain many of the proteins which are prone to aggregate and are responsible for causing PD, AD,

7.4 Role of Exosomes in the Pathogenesis

Creutzfeldt Jakob disease, and Amyotrophic lateral sclerosis (Brettschneider et al., 2015). Proteins like Aβ, tau, and α-synuclein have been reported to show prion-like activity in causing the pathological conversion of normal conformers of these proteins to those associated with disease. The aggregated nature and stable conformation of these proteins are resistant to proteolytic digestion. Many studies using cells and rat models came forward with evidence that the proteins causing neurodegeneration could be transmissible (Prusiner et al., 2015; Aguzzi and Rajendran, 2009). Although the accurate mechanism of transmission is yet to be discovered, various studies have revealed that it could be either by cell to cell communication or via tunneling nanotubes (Kanu et al., 2002; Gousset et al., 2009). A number of research studies have illustrated the involvement of exosomes in the transmission as neurodegenerative proteins were found to be secreted from the cell in association with exosomes (Fevrier et al., 2004). Due to their small size and relative stability, exosomes can cross the blood brain barrier (BBB) and, therefore, reveal bright perspectives toward diagnosis and as therapeutic tools for future neuro medicine (Aryani and Denecke, 2016; Jarmalaviciute and Pivoriunas, 2016; Howitt and Hill, 2016; Vella et al., 2016; Tsilioni et al., 2014; Wu et al., 2016; Lai and Breakefield, 2012). An exosomal biomarker signature has also recently been established to detect AD (Lugli et al., 2015; Cheng et al., 2015).

7.4.4 EXOSOMES IN METABOLIC DISORDERS The burden of metabolic disorders including type 2 diabetes, dyslipidemia, insulin resistance, and cardiovascular disease is exponentially increasing worldwide (Raj et al., 2014; Bhatti et al., 2016). Recent in vivo and in vitro studies demonstrated that exosomes secreted by a variety of cells play an important role in the regulation of the metabolic functions and may be responsible for the progression of some diseases (Lee et al., 2016). Exosomes are found to be rich in various biomolecules like proteins, mRNA, miRNA, noncoding RNA, and lipids. Recent studies have shown that exosomes isolated from biological fluids can be implemented as biomarkers for early diagnosis of metabolic diseases and can give an idea about the progression of the disease. Exosomes are capable of transferring DNA, RNA, and protein molecules which can regulate the metabolic functioning by interacting directly by transmembrane contact with the cell surface receptors of the nearby cells in remote areas (Aoki et al., 2007; Conde-Vancells et al., 2008; EL Andaloussi et al., 2013). Exosomes have the ability to perform vital functions on various platforms, including having a significant role in tumor progression (Rak and Guha, 2012), tissue regeneration (Timmers et al., 2011), enhancing the immune escape way and immune responses (Cai et al., 2012a; Simhadri et al., 2008; Chivet et al., 2012), transmission of neurological proteins (Bellingham et al., 2012; Emmanouilidou et al., 2010), and metabolic dysfunctions (Aswad et al., 2014).

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Amplification in the number of exosomes can lead to obesity and inflammatory complications (Feng et al., 2010; Kim et al., 2012). Exosomes released from the surface molecules of skeletal muscle, platelets, and T-cells contribute in metabolic dysfunctions and atherogenic tendencies (Aswad et al., 2014; Diamant et al., 2002). Previous studies linked the functioning of the exosomes with their number that was assessed to be higher in the plasma of type 2 diabetes mellitus (T2DM) patients having insulin resistance. Exosomes have the ability to organize insulin signaling which has become an emerging concept in the exosome-mediated regulation of metabolism in T2DM (Aswad et al., 2014; Safdar et al., 2016; Jalabert et al., 2016; Lee et al., 2015). Diverse complications associated with the T2DM represent miscellaneous patterns of exosomal biomolecules signifying exosomes that may contribute to the pathophysiology of type 2 diabetes and its complications (Lawson et al., 2016; Lee et al., 2016). A study reported that Exosomes-like vesicles released by adipose tissue can act as a mode of communication between adipose tissues and macrophages and subsequent development of insulin resistance in a mouse model (Deng et al., 2009). Moreover, visceral adipose tissue (VAT) derived exosomes are also functional in the intercellular transmission of signals as they possess adipokines (Lee et al., 2015). Skeletal muscle regulates the metabolism of the whole body and the exosomes released from it can facilitate the amendments in muscle homeostasis (Aswad et al., 2014). Keeping in view the merits of exosomes, efforts are being made to flourish them as novel prognostic, and even diagnostic, biomarkers, especially for the exosomes released from biological fluids. The presence of miRNA in blood, specific for the disease and condition/stage of illness, can act as a biomarker for prediction and diagnosing the complications associated with that particular disease (Jansen et al., 2013; Wang et al., 2014; Schulte et al., 2016; O’Neill et al., 2016). Exosomes secreted by various cells and tissues emerged as a new therapeutic strategy in cardiovascular diseases (Sahoo and Losordo, 2014; Davidson et al., 2016; Ibrahim et al., 2014; Ong and Wu, 2015; Cervio et al., 2015; Huber and Holvoet, 2015; Yellon and Davidson, 2014; Emanueli et al., 2015; Zhang et al., 2017; Zhao et al., 2015; Huang et al., 2015; Lawson et al., 2016; Suzuki et al., 2016; Xitong and Xiaorong, 2016). It has been reported that after myocardial infarction, the cardiac tissue discharges many soluble chemokines, cytokines, and growth factors; induce inflammatory responses; and recruit stem and progenitor cells to accelerate the repair process (Liu et al., 2016). Exosomes are reported to be involved in cardiac repair and regeneration by communication at intercellular and tissue levels (Sahoo and Losordo, 2014; Yuan et al., 2016). The exosomes from cardiomyocyte can transfect endothelial cells, stem cells, fibroblasts, and smooth muscle cells to induce cellular changes. Exosomes derived from DCs improve cardiac function via activation of CD4 1 T lymphocytes after myocardial infarction (Liu et al., 2016). A recent study demonstrated exosomes as potential alternatives to stem cell therapy in mediating cardiac regeneration (Ong and Wu, 2015).

7.6 Exosomes in Drug and Gene Delivery

7.5 EXOSOMES AS NANOCARRIERS Nanoparticle drug delivery systems offer many advantages like their ability to load high quantities (Natasha et al., 2014), sustained release of the loaded drug, ability to load both drug along with the adjuvant for the induction of costimulation within a particular nanocarrier (Amoozgar and Goldberg, 2015; Hamdy et al., 2011). Although there has been rigorous and thorough experimentation, partial accomplishments have been developed in clinical trials owing to deficiency in safety and efficiency of the target drug to the desired cells. Different types of nanocarriers have been investigated at length for the targeted drug delivery of drugs/genes to a specific site of cancerous tissue. Nanocarriers are most-exploited in this field because they are more permeable along with the ability to accumulate into tumors passively as well as having the capability of longer retention, for example, DCs. Macrophages and the primary cells are the natural phagocytotic involved in antitumor immunity and inflammatory response. Nano-drug delivery systems are promising platforms to deliver immunomodulatory compounds to these cells (Amoozgar and Goldberg, 2015). Exosomes, also called biological nanocarriers, are becoming visible as a promising alternative to this new concept of drug delivery (Ha et al., 2016; Aryani and Denecke, 2016). Exosomes are secreted by many types of cells, under both normal and pathological conditions. The matter of great interest is that exosomes are secreted by tumor cells and are much more in number compared with the normal cells (Thery et al., 2002b). RNA carried by exosomes could be exploited as drug and gene delivery systems; however, donor cells should not release exosomes with any immunomodulation ability and should be stable enough for the sufficient period to carry the cargo.

7.6 EXOSOMES IN DRUG AND GENE DELIVERY About 98% of drugs cannot cross the BBB. Even the nano-drugs that can solve this problem to some extent have associated issues of nanotoxicity and rapid drug clearance by the mononuclear phagocytic system (MPS) (Pardridge, 2012). Polyethylene glycol is used to solve this problem, but decreases the drug distribution to the brain and the interaction between target cells (Peng et al., 2013). These types of complications can be handled by using exosomes as a drug delivery system as it is a body’s natural product and can be personalized to cross the BBB and increasing the drug distribution to the brain by decreasing the MPS drug clearance (Yoshida et al., 1992). The morphology of the exosomes can be exploited in a manner to facilitate drug delivery as they can be used as vehicles because of their many advantages over other drug delivery systems in practice like liposomal and nano-particulate drug delivery systems (Ferguson and Nguyen, 2016). The phenomenon of communication between cells is an integral part of the multicellular organisms for the maintenance of homeostasis. Gap junctions

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connect the nearby cells and distant intercellular communication can be facilitated via hormones by sending signals through circulatory systems. EVs can provide many advantages in distant cell communication as EVs can carry a cellular cargo of lipids, proteins, receptors, and active molecules to recipient cells (Lai et al., 2013).

7.6.1 DRUG DELIVERY VEHICLES FOR SMALL MOLECULES Liposomal and the polymeric nanoparticle systems are preferred systems for drug delivery (Sercombe et al., 2015). Liposomes, a synthetic vesicle of the phospholipidic membrane, have the capacity of self-assembling in various sizes and shapes in an aqueous medium whereas polymeric nanoparticles can entrap, encapsulate, or attach drug molecules (Agrawal et al., 2014; Raemdonck et al., 2014). Both systems have been used for delivering anticancer, antifungal, and analgesic drugs. The main advantage of liposomes used as the delivery system is their stability in circulation for a longer duration without causing toxicity and, moreover, their capability of evading the immune system (Li et al., 2015; Aryani and Denecke, 2016). Polymeric nanoparticles have better stability compared to liposomes, but biocompatibility and toxicity issues are of major concern. Fig. 7.3 shows the role of exosomes as nanocarriers for the delivery of small molecules including miRNA, small interference RNA (siRNA), peptides, and drugs. Above all, exosomes come with all the features of longer duration in the circulatory system, the ability to target the specific tissue, enhanced biocompatibility

FIGURE 7.3 Exosomes as nanocarriers for drugs, siRNA, or peptide delivery. Exosomes are nanosized and stable molecules capable of targeted delivery of nucleic acids, proteins, and drugs and, therefore, can be exploited for gene therapy and drug delivery systems. siRNA, Small interference RNA.

7.6 Exosomes in Drug and Gene Delivery

along with the minimal inherent toxicity issues. Hence exosomes are preferred over previously used drug delivery systems due to their unbeatable characteristics (Turturici et al., 2014; Rani and Ritter, 2016). Extensive research has been done using exosomes as vehicles for therapeutic drug delivery. Exosome complexes with curcumin enhance efficacy and safety when administered in cancer patients (Dhillon et al., 2008). Experiments on exosomes carrying curcumin demonstrate the increased solubility, stability, bioavailability, and antiinflammatory activity both in vitro and in vivo. In in vitro experiments, when macrophages were treated with exosomal curcumin, the production of the TNF and IL-6 is less in comparison to those treated with curcumin alone, proving the antiinflammatory capability of exosomes. In lipopolysaccharide (LPS) induced a septic shock model in which CD11bþGr-1þ cells increases response to LPS in the lungs and leads to acute lung inflammation. Exosomal curcumin showed significantly longer survival compared with mice treated with curcumin alone, again verifying the fact that exosomes enhance the antiinflammatory characteristics of curcumin. Exosomes illustrate the potential of brain drug delivery across the BBB by carrying paclitaxel and doxorubicin drugs and also demonstrate the transport mechanism in a zebrafish model (Yang et al., 2015). Exosomes were isolated from the glioblastoma astrocytoma U-87 MG, endothelial bEND.3, neuroectodermal tumor PFSK-1, and glioblastoma A-172 loaded with rhodamine 123, paclitaxel, and doxorubicin. Brain tissue was examined for the presence of the rhodamine 123 fluorescence and drug distribution observed in the brain region of the zebrafish embryos suggested the ability of exosomes to deliver the drug across the BBB. Further, in subsequent experiments, the primary brain cancer model was developed and anticancer drugs loaded with or without exosomes were applied. Drugs loaded with the exosomes showed the therapeutic efficacy of the exosomes better than the drug alone. Exosomes have the potential to deliver the drugs to the brain tissue by crossing the BBB and helps tremendously in curing brain cancers and other neurological disorders (Ha et al., 2016).

7.6.2 DRUG DELIVERY VEHICLES FOR PROTEINS Exosomes can also have the ability to deliver molecules bigger in size. Mounting evidence shows that exosomes loaded with the antioxidant protein catalase was successfully delivered across the BBB resulting in an improved disease state in PD (Haney et al., 2015). Patients suffering from PD have lower levels of antioxidant enzymes like catalase and superoxide dismutase levels and cause oxidative stress along with neurodegeneration (Ambani et al., 1975; Riederer et al., 1989; Abraham et al., 2005). Catalase can neutralize one million free radicals per second per molecule in a single catalytic reaction cycle (Haney et al., 2015), but the delivery of catalase across the BBB is a big task. Exosomes have undertaken this tedious task and fulfilled it efficiently, so are a promising option in PD therapy.

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7.6.3 DRUG DELIVERY VEHICLES FOR NUCLEIC ACIDS Exosomes are exceptionally excellent delivery systems which can also carry DNA and RNA-like big and heavy molecules to the target cells, thereby instigating genetic modification in the biological processes. This strategy can be employed as a promising tool for delivering genetic material and altering the gene expression in certain diseases and help improve gene therapy.

7.6.4 SMALL INTERFERENCE RNA siRNA is a molecule with low stability and it degrades quickly. It can be used to change gene expression and can be very useful in gene therapy to alter pathological symptoms. Exosomes can deliver siRNA to the cell of interest (Alvarez-Erviti et al., 2011; Wahlgren et al., 2016). A recent study explored the ability of exosomes to transfer nucleic acids to cells in a specific manner using elf exosomes loaded with chemically modified siRNAs and displaying specific targeting molecules (Alvarez-Erviti et al., 2011). The DCs were modified to express LAMP-2b fused to the central nervous system-specific RVG peptide that specifically binds to the acetylcholine receptor. Exosomes were loaded with exogenous siRNA by electroporation and, after in vitro experiments, were injected into mice together with a series of control exosome preparations. The injection of RVG exosomes resulted in a significant knockdown of GAPDH mRNA in the brain regions expressing the target of the RVG ligand-nicotinic acetylcholine receptors. These results not only showed the therapeutic potential of RVG exosome technology for new therapeutic approaches against neurodegenerative diseases, but also strongly supported the use of implemented and innovative exosome technologies for targeting therapies for a number of diseases. The siRNA delivery through exosomes has numeral benefits over typical viruses, lipid nanocarriers, and polycationic delivery mediators currently in practice (van den Boorn et al., 2011). Most importantly, exosomes deliver their load straight into the cytosol, evading the requirement for endosomal escape, while their inertness circumvents clearance in the extracellular environment (van den Boorn et al., 2013). Many studies reported exosomes as an efficient therapeutic vehicle for exogenous and to T-cells and monocytes (Wahlgren et al., 2012). There is no other vehicle available for delivering genetic material, but exosomes proved to be safe, efficient, and target specific. Electroporation was found to be the best method for successful introduction of siRNA (Wahlgren et al., 2016). Exosomes with siRNA in recipient cells showed a decrease in MAPK1 expression indicating downregulation of the specific gene and successful gene silencing. Exosomes delivered siRNA against RAD51, a eukaryotic gene protein which assists in DNA repair and stops the proliferation of cancer cells (Shtam et al., 2013). Recent studies indicated that exosomes could deliver the exogenous molecules to the cells with all the functions still intact (Banizs et al., 2014).

7.6 Exosomes in Drug and Gene Delivery

7.6.5 MICRORNA miRNAs are noncoding RNAs with nonprotein nucleotides and are present in eukaryotic cells and considered as key functional elements. The exosomes are natural carriers of miRNA that could be exploited as an RNA drug delivery system. miRNA-containing exosomes are found in a variety of body fluids and cell regulate gene expression in the target cells (Kosaka et al., 2010; Thery, 2011). miRNA bind to the complementary sequences on the mRNA and function to control the posttranslational gene expression (Bartel, 2004, 2009). A recent study showed that exosomes can efficiently deliver miRNA to epidermal growth factor receptor (EGFR)-expressing breast cancer cells (Ohno et al., 2013). The epidermal growth factor and EGFR-specific peptide (GE11) were incorporated onto the surfaces of exosomes that carried let-7a in order to deliver let-7a to EGFRexpressing cancer tissue. Mounting evidence suggests that miRNA, like let-7a, functions as a tumor suppressor and prevents the development of cancer by reducing RAS and high-mobility group AT-hook protein (HMGA2) expression (Ohno et al., 2013). In this study, modified exosomes with GE11 peptide or EGF on their surfaces delivered miRNA to EGFR-expressing cancer tissues; intravenously injected exosomes targeting EGFR delivered let-7a specifically to xenograft breast cancer cells in RAG2 2 / 2 mice. These data indicate that exosomes targeted to EGFR-expressing cells may provide a platform for miRNA replacement therapies in the treatment of various cancers. Numerous human tumors of epithelial origin display elevated EGFR expression, suggesting that EGFR could serve as a receptor target in cancer drug delivery systems (Gazdar, 2010; HarichandHerdt and Ramalingam, 2008; Huang and Harari, 1999; Woodburn, 1999). Table 7.1 shows the therapeutic cargo molecules loaded into exosomes in cancer (Johnsen et al., 2014). Recent studies also suggested exosomal miRNA as a biomarker of AD (Lugli et al., 2015; Cheng et al., 2015) and a variety of cancers including acute myeloid leukemia, colorectal cancer, and hepatocellular carcinoma (Hornick et al., 2015; Matsumura et al., 2015; Ogata-Kawata et al., 2014; Sugimachi et al., 2015). Among proteins, lipids, DNA, and RNA, the miRNA is found in higher concentrations (Goldie et al., 2014) and could be transferred between cells via exosomes (Valadi et al., 2007). Exosomes carrying miRNA released from the cells circulate and can transfer it to distant cells where the miRNA becomes functional in the recipient cells. Some studies done in both immune cells and other cell types demonstrated that transferred miRNAs inhibit target mRNAs in recipient cells (Montecalvo et al., 2012; Kosaka et al., 2010; Mittelbrunn et al., 2011; Katakowski et al., 2010; Alexander et al., 2015). A decade of research has identified many exosomal miRNAs which are involved in the diagnosis, therapeutics, and pathophysiology of many diseases including cancer, neurodegenerative diseases, metabolic disorders, cardiovascular diseases, and immune disorders.

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Table 7.1 Various Therapeutic Cargo Molecules Loaded into Exosomes for Targeted Cancer Therapy Study

Cargo

Interfering RNAs Shtam et al. (2013) Wahlgren et al. (2012) Alvarez-Erviti et al. (2011) Pan et al. (2012) Chen et al. (2014) Bryniarski et al. (2013) Zhang et al. (2010) Katakowski et al. (2013) Kosaka et al. (2012) Pan et al. (2012) Xin et al. (2012) Ohno et al. (2013) Munoz et al. (2013)

siRNA against RAD51 and RAD52 MAPK1 siRNA GAPDH siRNA and BACE1 siRNA shNS5b, shCD81 miR-214 miR-150 miR-150 miR-146b miR-143 miR-122 miR-133b Let-7a Cy5-anti-miR-9

Other Types of Therapeutic Cargo Tian et al. (2014) Jang et al. (2013) Hood et al. (2014) Mizrak et al. (2013) Maguire et al. (2012) Zhuang et al. (2011) Sun et al. (2010)

Doxorubicin Doxorubicin SPION5 CD fused with UPRT and EGFP Adeno-associated viral vector Curcumin and JSI-124 Curcumin

CD, Cytosine deaminase; EGFP, enhanced green fluorescence protein; siRNA, small interference RNA; SPION, superparamagnetic iron oxide nanoparticles; UPRT, uracil phosphoribosyltransferase.

7.7 CONCLUDING REMARKS AND FUTURE PERSPECTIVES Exosomes are nanosized vesicles secreted by a variety of cells and have ideal features as nanocarriers for drug and gene delivery. Exosomes are secreted by a variety of cells and body fluids including serum, plasma, urine, semen, breast milk, sweat, synovial fluids, etc. They are composed of a lipid bilayer, proteins, DNA, RNA, enzymes, and many other essential molecules. Due to their normal biological functioning in the cell, exosomes help cells to regulate other cells at a distance and communicate with them. Exosomes are known to be associated with diverse pathologies and represent a variety of functions like delivering biomolecules such as mRNAs, miRNAs, siRNA, proteins, and drugs to the recipient cells by communication at intercellular and tissue levels. Exosomes display a wide variety of functions in the cell including cell cell communication, diagnostic markers, and their potential role in therapeutics. Some exosomes possess

References

immunostimulatory or immunosuppressive effects which can be used as immunotherapies for cancer or autoimmune diseases. Primary studies have also reported the successful delivery of chemotherapeutic drug-loaded exosome mimetic MVs to tumor tissue in vivo and in vitro. Furthermore, exosomes are involved in various pathologic conditions including AD, PD, and metabolic disorders. Emerging evidence has revealed the promising therapeutic potential of exosomes as effective nano-vaccines and immunological treatment for inflammatory diseases. Exosomes are also known to play important role as diagnostic biomarkers of various diseases. In addition, they are considered in many clinical studies as a delivery system to transport RNA, protein, and drug molecules as they can easily cross the BBB. However, developing a strategy to produce exosomes with desirable components and less undesirable effects may have great potential for clinical application. More research is required to fully illucidate the use of exosomes in diagnostic and therapeutic measures.

CONFLICT OF INTEREST None declared.

ACKNOWLEDGMENTS JSB and GKB were financially supported by University Grant Commission, New Delhi, India under Raman Post-Doctoral Research Fellowship in United States [F.No. 5-82/2016 (IC)] and Rajiv Gandhi Post Doc Fellowship (PDFSS-2011-12-SC-CHA-3405), respectively.

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