Extracellular Vesicles Based Drug Delivery: History
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Subjects: Oncology | Physiology | Biochemistry & Molecular Biology
Contributor:
Isha Gaurav

Extracellular vesicles (EVs) play major roles in intracellular communication and participate in several biological functions in both normal and pathological conditions. Surface modification of EVs via various ligands, such as proteins, peptides, or aptamers, offers great potential as a means to achieve targeted delivery of therapeutic cargo, i.e., in drug delivery systems (DDS). This study summarizes recent studies pertaining to the development of EV-based DDS and its advantages compared to conventional nano drug delivery systems (NDDS). 

  • extracellular vesicles
  • exosomes
  • drug delivery systems
  • targeted delivery

1. Introduction

A drug delivery system (DDS) consists of various formulation which enable therapeutic substance to reach the desired site of action specifically without going to non-target sites [1]. In nano drug delivery systems (NDDS), different biodegradable and biocompatible materials with size approximately 10-100 nm are utilized as nanocarriers [2][3]. These nanocarriers can be either natural or synthetic polymers, lipids, and metals such as nanoparticles [1][2][3][4]. Although NDDS have been used with several drugs including anti-cancer drugs [5][6][7], very few have been approved for use in humans by the Food and Drug Administration [8]. Cytotoxicity and rapid clearance of most of the synthetic NDDS via the mononuclear phagocyte system or reticuloendothelial system have been major bottlenecks in their transition from bench to bedside in clinical setting [9][10]. Several approaches have been employed to modify the nanoparticles (NPs). One example is coating the NPs with polyethylene glycol (PEG); this enhanced circulation time but impeded interaction between the target cells or tissues and the NDDS, thereby interfering with their biodistribution [11][12][13]. Another approach is to look for natural DDS, which could be expected to yield higher therapeutic value owing to their better in vivo biocompatibility as compared to the synthetic NDDS [14][15][16]. Extracellular vesicles (EVs) are natural nanovesicles released from most cells and biofluids; they carry various cargo including nucleic acids, proteins, and lipids [17]. EVs have attracted tremendous attention in the context of NDDS due to their ability to facilitate intracellular communication and the transportation of cargo to the target recipient cells [18][19]. Based on their size range and biogenesis, EVs are categorized into three major types, namely exosomes, microvesicles (MVs), and apoptotic bodies (ABs) [20]. Exosomes are of endocytic origin. They have sizes in the range of 30–100 nm; structurally, exosomes are composed of a lipid bilayer carrying cargoes of different composition including functional proteins, DNA, mRNA, miRNA, and lncRNA (Figure 1) [21][22][23].

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Figure 1. Representative structure of an exosome and its composition.

The biogenesis of exosomes takes place by inward budding of the plasma membrane that forms the endosome vesicle, and the multivesicular bodies (MVBs). MVBs fuse with lysosomes and degrade or fuse with the plasma membrane and form exosomes which are released from cell into extracellular space (Figure 2A) [24][25]. They are released from various cell types like red blood cells, platelets, lymphocytes, dendritic cells (DCs), epithelial cells, adipocytes, fibroblasts, neural cells, stem cells, and cancer cells [26]. They have also been found in various biofluids such as blood, plasma, urine, cerebrospinal fluid (CSF), milk, amniotic fluid, malignant ascites, saliva, and synovial fluid [27][28][29]. They play a major role in cell-to-cell communication in the signalling pathways of both physiological and pathological processes [30], and transferring molecules such as proteins and RNA from donor cells to recipient cells [27][31]. Various specific proteins are present on the surface of exosomes, such as tetraspanin proteins (CD9, CD63, and CD81) [31], lysosomal protein (Hsp70), tumor sensitive gene 101 (Tsg101), and fusion proteins (annexin, and flotillin) [32]. These proteins are associated with the endosomal pathway, and are characteristic of exosomes, distinguishing them from MVs and ABs. MVs are another set of EVs with size in the range of 100–1000 nm; they are formed and released by budding off cell membrane [33]. In contrast, ABs are in the size range of 50–5000 nm, and are released from cells undergoing apoptosis [34] as shown in Figure 2B, C. Some scientists have subdivided the category of EV into subtypes, partially based on size, marker and biogenesis [35][36]; in this review the term EV refers to the general category, unless we specifically refer to a subgroup.

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Figure 2. Biogenesis pathways followed by different types of EVs, namely exosomes, MVs, and ABs. (A) MVBs fuse with lysosomes and degrade or fuse with the plasma membrane and form exosomes which are released from cell into extracellular space. (B) MVs are a set of EVs with size in the range of 100–1000 nm; they are formed and released by budding off cell membrane. (C) ABs are in the size range of 50–5000 nm, and are released from cells undergoing apoptosis.

A diverse range of studies have been carried out exploring the application of EVs in drug delivery. It has been found that miRNA and protein can be loaded on EVs and delivered to t tumor cells [37][38]. EVs also show the capability to inhibit tumor growth by delivering chemical drugs [39]. Interestingly, EVs can avoid phagocytosis by macrophages and prolong the half-life of chemical drugs in comparison to artificial NDDS, and are considered as the natural carrier of chemical drugs to improve the efficiency of biological drug delivery [40][41][42]. Previous review articles have covered various aspects of EVs in NDDS. This review updates those summaries with an in-depth discussion of the latest methods for surface modification of EVs, the importance of cell origin, and the importance of loading efficiency in EV-based targeted drug delivery systems. Here we shed light on the structural similarity between liposome and EVs, and their different roles in targeted delivery.

2. How Crucial Is the Origin of Exosomes for Drug Delivery?

There are various sources of EVs which can be employed for developing DDS (Figure 3). To achieve the desired effect and to avoid any potential harmful effects, it is necessary to understand the pros and cons of selecting any particular source. For example, the proportion of lipid to surface protein in an EV differs, depending on the source [43]. This proportion can affect certain properties that are crucial for effective delivery, and thus should be considered when selecting a source. It has also been found that the proportion of certain lipids is enhanced in exosomes as compared to the amount of lipids in their donor cells, such as sphingolipid, phosphatidylserine, phosphatidylinositol, and cholesterol. These lipids facilitate in enhancing the rigidity of exosomal membrane [44]. Another factor to consider is the relationship between surface proteins and target cells. Some sources produce EVs with surface proteins that are detrimental to the recipient target cells. A third factor is biocompatibility; and finally yield should also be taken into consideration while making selection of donor source cells for isolation of EVs for developing into EVs-based DDS.

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Figure 3. Different sources of EVs for developing EV-based DDS, their advantages, and disadvantages.

2.1. Choice between Autologous and Heterologous EVs

The choice between autologous and heterologous (also referred as allogenic) EVs for developing into DDS is one of the crucial factors for effective delivery. It has been found that the uptake of autologous EVs and the uptake of heterologous EVs by target recipient cells differ distinctly. As the compositions of EVs have been reported to mimic their parent cells, the selection of heterologous EVs may induce an immune response in the target recipient cells. Therefore, theoretically, autologous EVs may be more suitable for therapeutic purposes [45]. In practice, however, heterologous EVs from MSCs have been found to be safe and reliable for therapeutic purposes. Still, we shouldn’t forget about autologous EVs, for example, pathological tissues are generally considered waste; however, if the EVs from these tissues could be isolated and their disease-causing cargo removed, these EVs could be valuable DDs [46]. Lessi et al. demonstrated that human primary macrophage-derived EVs could deliver drugs efficiently, [47], suggesting that autologous EVs derived from peripheral blood-derived primary monocytes could be suitable as theranostic agents. The safety profile of these EVs needs to be assessed before developing them into DDS; however, some evidence indicates they are safer than EVs derived from plasma [48].

2.2. Tumor-Derived EVs

Tumor-derived EVs (TEVs) have been employed by many research groups for drug delivery [49][50]. TEVs have several advantages compared to other delivery carriers. For example, tumor cells release significantly high numbers of EVs [51], suggesting their suitability for studies requiring large amounts of EVs. In addition, TEVs carry MHC class-I molecules and antigens specific to the originating tumor cells. Moreover, TEVs can induce immune response against cancer cells by delivering antigens to DCs [52]. Interestingly, the tetraspanin proteins, common markers for exosomes, have been found to bind with various ligands in a diverse range of tissues, suggesting their suitability for targeted delivery [53]. TEVs from melanoma patients have been found to increase the release of myeloid-derived suppressor cells (MDSCs), crucial for avoiding immune recognition [54][55]. It is striking that although TEVs have been shown to have potential for targeted delivery, there is also a chance that they can initiate tumor progression due to various of their constituents, such as urokinase plasminogen activator, which can promote cancer cell invasion, and adhesion modulators like vimentin, and annexin A1 [56]. Therefore, again, selection of appropriate source for isolating EVs is a crucial factor for developing successful and effective EV-based targeted DDS.

2.3. Immune Cell-Derived EVs

Another important source from which EVs can be isolated are immune cells. For example cells like macrophages and monocytes have gained attention for EV-based immunotherapy [57][58]. Immune cell derived EVs (IEVs) can evade phagocytosis, a clearance mechanism, which is a major limitation for most of the other types of EVs. Therefore, IEVs possess longer circulation time and better efficacy [59]. Importantly, the DC-derived EVs (DCEVs) seem to have a great potential as various clinical studies have demonstrated their effectiveness on different cancers. DCEVs play a major role as intercellular communicators in adaptive immunity for modulation of immune responses. Therefore, most of the researches related to DCEVs are about immunotherapy of cancer leading to clinical advantage [60][61]. Notably, in a Phase-I clinical trial, Escudier et al. reported the feasibility and safety of administering DCEVs pulsed with MAGE 3 peptides for immunization in melanoma patients under stage- III/IV [58]. DCEVs have also been found to promote tumor rejection via transporting peptide-MHC complexes from DCs (exposed to an antigen) to other DCs (not exposed to same antigen) [57][62][63].

2.4. Biofluid-Derived EVs

EVs derived from biofluids such as plasma [64], and ascites [65], have shown potential as delivery carriers. Biofluid-derived EVs have several advantages as delivery carriers. For example, unlike cell culture-derived EVs, plasma-derived EVs are enriched with lyso-phospholipids and do not contain phosphatidylserine (PS). The absence of PS on the surface of plasma-derived EVs prevent their removal from circulation [64][66]. In addition, plasma-derived EVs can cross the blood-brain barrier (BBB), which suggests their applicability for brain delivery [64]. Ascites-derived EVs along with granulocyte–macrophage colony-stimulating factor have been found to be safe and effective for immunotherapy of colorectal cancer [65]. It has also been reported that human peripheral blood-derived EVs loaded with miRNA have potential for treating cardiac diseases [67]. Another study showed that EVs in peripheral blood can be important mediators of lung injury via exosomal shuttling of miR-155 [68]. Blood EVs have been shown to be crucial for targeting brain disease. For example, dopamine-loaded blood EVs can be used as delivery platform in treating Parkinson’s disease and other central nervous system-related disorders [69]. Urine- and saliva-derived EVs have not been much explored for their therapeutic potential as delivery carriers; however, they have been extensively studied for developing biomarker of different diseases including cancer [70][71]. Conclusively, biofluids such as blood and ascites are great sources of EVs for developing novel DDS.

2.5. Plant and Bovine Milk-Derived EVs

Due to safety concerns related to TEVs and IEVs, scientists have explored the applicability of plant-derived EVs (PEVs) as DDS, such as grape-derived EVs [72] or bovine milk-derived EVs (BMEVs) [73]. There are several advantages of using PEVs as DDS, including better safety, consistency of source, scalability for large production, and relative cost effectiveness [72]. Several research groups have isolated EVs from different plants or food sources and showed a diverse range of applications [74]. For example Ju et al. demonstrated that grape- derived EVs are useful in protecting intestinal damage in mice via facilitating growth and differentiation of intestinal stem cells [72]. Subsequently, Wang et al. demonstrated that modification of grapefruit derived EVs improved their ability to target tumors and loaded those EVs with doxorubicin and curcumin. Interestingly, those EVs were found to be effective against inflammation in vivo [75]. Bovine milk is another important source of EVs for DDS. Mungala et al. demonstrated the enhanced activity of various therapeutic cargo loaded BMEVs against lung cancer in vitro and in vivo. They further showed that modification of BMEVs with folate could enhance tumor-targeting ability as compared to the free drug [73]. Recently, because many clinical trials for the treatment of Alzheimer’s disease (AD) using synthetic drugs have failed [76][77][78], scientists are trying to develop targeted delivery using EVs and developing precision medicine-loaded EVs for the treatment of AD [79][80]. Plant-derived traditional medicine have been studied in preclinical models of AD [81][82][83]. Targeted delivery of plant-derived bioactive components using EVs could be more effective for the treatment of AD.

3. How Does Loading Efficiency Play a Crucial Role in EV-Based DDS?

Loading therapeutic cargo into EVs is one of the crucial parts in the process of developing EV-based DDS. The high loading efficiency of EVs ensures better bioavailability of the cargo when it reaches the target site. The major factors that need consideration while loading any cargo onto EVs are: how better encapsulation or loading efficiency can be achieved, how the structural integrity of EVs can be maintained, and how the functional properties of the therapeutic cargo can be maintained.

Therapeutic cargo such as proteins, drugs, or small nucleic acids such as miRNA can be loaded in two different ways. First, the therapeutic cargo can be incorporated into donor cells, followed by isolation of EVs; this is referred to as in vitro loading [84]. Second, the therapeutic cargo can be loaded after isolation of EVs via various methods including incubation, sonication, electroporation, extrusion, permeabilization, or the freeze-thaw method; this is referred to as ex vivo loading (Figure 4) [59]. In the simple incubation method, EVs are incubated with drugs, and the drugs enter EVs via diffusion due to the concentration gradient. Incubation is found to be suitable for loading hydrophobic drugs as they interact with lipid layers of EVs’ membranes [59][85]. One disadvantage of simple incubation is low loading efficiency. Another method of loading is incubation of drugs with donor cells, followed by isolation of EVs [84]. Table 1 summarizes different loading methods with their advantages and disadvantages. The physicochemical properties of the therapeutic cargo partially determine what method is employed for their encapsulation in EVs. For example hydrophobic drugs such as curcumin can be loaded within the inner layers of fatty acid via incubation, whereas hydrophilic molecules including siRNA, miRNA can be loaded by forming transient pores on the membrane of EVs via methods like electroporation [16][86][87].

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Figure 4. Different methods for loading therapeutic cargos in EVs for developing EV-based delivery systems.

Table 1. Different techniques for loading cargos in EVs with advantages and disadvantages.

Loading Methods Steps Involved Advantages Disadvantages Ref.
Electroporation Phospholipid bilayer of EVs are disorganized by an electric field, creating pores in the membrane which allow the passage of drug to vesicle. Loading with large molecules is possible Disrupts integrity of EVs; Low loading efficiency [86][88][89][90]
Sonication Exosomes derived from donor cells are mixed with drug and sonicated through probe sonicator which permits the drug to flow into exosome Increased loading efficiency; applicable for small RNAs Potential deformation of membrane of EVs;
Not efficient for hydrophobic drugs.		 [91][92]
Extrusion Exosomes are mixed with drug and loaded into syringe-based lipid extruder and extruded through membrane with 100–400 nm pore size at controlled temperature. High drug loading efficiency Potential deformation
of membrane.		 [91]
Freeze/Thaw Method Exosome are mixed with drug and incubated, subsequently frozen at −80 °C or in liquid nitrogen and are thawed at room temperature. Medium loading;Fusion of membranespossible Exosomes may aggregate;
Low loading efficiency		 [91]
Saponin-Assisted Loading Saponin is incubated with exosomes to generate pores in their membrane by interacting with cholesterol which leads to increased membrane permeability High drug loading compared to the other methods used in early reports Generates pores in exosomes;
Saponin can cause haemolysis;
Toxicity concerns;
Saponin concentration control & washing required		 [59][93][94]
Dialysis Exosomes mixed with drug are dialyzed by stirring to obtain drug loaded exosome. Promotes loading efficiency Poor cellular uptake;
No substantial impact on photodynamic effect		 [95]

Recently, membrane permeabilization of EVs has been found to be a promising method for enhancing the loading efficiency of EVs. Saponin has been shown to be particularly effective in enhancing the loading of different cargos in EVs from various sources. Being a surfactant, saponin is able for form a complex with cholesterol in the membranes of cells and create pores, thereby facilitating permeabilization [93]. Haney et al. demonstrated that loading efficiency of catalase into exosomes can be enhanced via incubation with saponin, as compared with simple incubation technique. Interestingly, the activity of catalase was not affected by the saponin [59]. Another recent research showed that passing saponin through the microfluidic channels enhances loading of doxorubicin in glioma stem cell-derived exosomes as compared with other conventional methods. The authors reported two different microfluidic channels; one linear. and another sigmoid, which suggests that designing advanced microfluidic channels along with using permeabilizing agent may have a synergistic effect to achieve augmented efficiency of loading cargoes in EVs [16][96]. Fuhrmann et al. showed that incubation of a small hydrophilic molecule, porphyrin, with saponin could enhance the loading efficiency as compared with a passive loading technique excluding saponin [94]. Nevertheless, there are some concerns associated with the use of saponin for in vivo purposes because of its hemolytic activity [93].

This entry is adapted from the peer-reviewed paper 10.3390/molecules26061544

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