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Ali, N.B.;  Razis, A.F.A.;  Ooi, D.J.;  Chan, K.W.;  Ismail, N.;  Foo, J.B. Extracellular Vesicles as Drug Delivery Agent. Encyclopedia. Available online: https://encyclopedia.pub/entry/24831 (accessed on 18 December 2025).
Ali NB,  Razis AFA,  Ooi DJ,  Chan KW,  Ismail N,  Foo JB. Extracellular Vesicles as Drug Delivery Agent. Encyclopedia. Available at: https://encyclopedia.pub/entry/24831. Accessed December 18, 2025.
Ali, Nada Basheir, Ahmad Faizal Abdull Razis, Der Jiun Ooi, Kim Wei Chan, Norsharina Ismail, Jhi Biau Foo. "Extracellular Vesicles as Drug Delivery Agent" Encyclopedia, https://encyclopedia.pub/entry/24831 (accessed December 18, 2025).
Ali, N.B.,  Razis, A.F.A.,  Ooi, D.J.,  Chan, K.W.,  Ismail, N., & Foo, J.B. (2022, July 05). Extracellular Vesicles as Drug Delivery Agent. In Encyclopedia. https://encyclopedia.pub/entry/24831
Ali, Nada Basheir, et al. "Extracellular Vesicles as Drug Delivery Agent." Encyclopedia. Web. 05 July, 2022.
Extracellular Vesicles as Drug Delivery Agent
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27123941

Extracellular vesicles (Evs) can be found in all biological fluids, making them the perfect non-invasive diagnostic tool, as their cargo causes functional changes in the cells upon receiving, unlike synthetic drug carriers. EVs last longer in circulation and instigate minor immune responses, making them the perfect drug carrier.

exosomes extracellular vesicles biomarkers functional foods diagnostics

1. Introduction

Extracellular vesicles (Evs) were first studied and described in 1946 [1] and once were regarded as a cellular waste [2]. These EVs gained considerable attention throughout the years [3] due to the active mechanism of their release from the cells [4]. These sacs were described as extracellular vesicles [5].
A recommended definition by the International Society for Extracellular Vesicles (ISEV) advised using the term extracellular vesicles as the characteristic label for particles released naturally from the cells, distinct by a lipid bilayer, and do not replicate. The short term is EVs [6]. In order to study EVs, the process should undergo characterization to identify the transmembrane luminal protein; the characterization process should include but not be limited to zeta potential, electron microscopy, and flow cytometry [7]. EVs have been described as the novel communication method between cells, either on a long or short-range signaling requirement [8]. EVs are heterogeneous sacs of membranous vesicles released from the cells into the surrounding environment [9].
The recognized role of EVs is to carry a molecular cargo including RNA and surface markers [10] originating from the mother cell and reflect their status [11] to be delivered to the receiving cells. Organisms that range from prokaryotic cells to higher eukaryotes can produce EVs. In mammals, all kinds of cells release EVs [12]. An increasing number of studies focused their interest in plant-derived EVs as therapeutic agents since plant source materials retain less toxic effects than chemotherapeutic-based therapy [13].

2. Classification and Biogenesis of EVs

ISEV has classified EVs based on their size into two prominent families; large EVs (200 nm) and small EVs (40–150 nm) [14]. These fluid-filled sacs can also be classified based on their biogenesis [5]. Moreover, it can be categorized and termed without complying with the standard definition [7]. The release mechanism (Figure 1) is a controlled process; lipid and lipid metabolite enzymes play the most significant role in this process [15]. There are three ways by which the cells release EVs [16].
Figure 1. All cells release EVs, the mechanism of EVs formation determines its type, microvesicles released after budding of the plasma membrane (right-bottom corner), and exosomes (left-bottom corner) released from MVBs that formed inside the cell from early endosomes. Its cargo is loaded upon maturation (top corner illustrates EVs cargo). EVs can also be classified according to size; exosomes are the smallest, and apoptotic bodies are the largest.
  • Outward budding of the plasma membrane (shedding microvesicles, MVs) happens when the plasma membrane is reacting to external incitements such as inflammatory cytokines that provoke a response from the cell [17], leading to activation of the plasma membrane that will eventually release sacs 100–1000 nm in diameter that are released into the external surroundings including microparticles and microvesicles [18].
  • Inward budding of the endosomal membrane (early endosomes) results in the formation of multivesicular bodies (MVBs); these small size particles range in diameter 30–200 nm [18] and 30–150 nm [19]. The releasing mechanism of these MVBs starts by forming a sac inside the cell containing vesicles derived from the mother cell; eventually, these sacs will emerge with the plasma membrane and be released into the extracellular space, becoming exosomes [20].
  • Apoptosis-derived EVs (ApoBDs). In this case, the vesicles are large in diameter (800–5000 nm); the mechanism of release occurred during programmed cell death [21]; eventually, these vesicles will be released into the extracellular space and become another type of EV [22].
Lázaro-Ibáñez et al. [23] suggested that there is more to EVs than a sole classification into the formerly mentioned classes, stating that EVs could be allocated into further subpopulations. For instance, when the vesicles were recently examined by TEM, the EVs were described as cup-shaped particles with no indication of their cargo. Furthermore, cryo-TEM technology was used to characterize EV subpopulations. The technique confirmed the presence of cup-shaped vesicles when negatively stained; some have a single membrane smaller than 100 nm [24].
Different EV types can be produced by a single cell exhibiting diversity within the subtypes. Various subcellular locations produce subtypes of EVs, either similar or distinct [25].

3. EV Cargo and Uptake

Both apoptotic and healthy cells release these sacs (vesicles) containing protein, including plasma membrane and endosomal protein [26], lipids [27] most commonly cholesterol, ceramide, sphingolipids, and phosphatidylserine [28], mRNA, miRNA [29], tRNA, Y RNA [2], DNA [23], ssDNA, mtDNA, dsDNA [30] and sugars obtained from the cell f origin [10].

3.1. EV RNA

RNA sorting into EVs is not fully understood, but several mechanisms could achieve the process. For example, the selective loading of miRNA into EVs is facilitated by RNA-binding protein, such as SUMO protein (hnRNBA1); this protein will identify GAGAG motifs of the miRNA and selectively load them into EVs. Furthermore, the production of neutral sphingomyelinase 2 (nSMase 2) by ceramide significantly impacts loading miRNA into EVs [25]. Another example, in liver functional cells hepatocyte, the synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP) is able to recognize GGCU motif in particular miRNA and augment their loading into EVs. Leading to the understanding that RNA binding proteins regulate the internalization of RNA inside EVs via miRNA-conserved motifs [31]. Once inside the recipient cell, EVs will release their cargo that will control gene expression through de novo translation and post-translational regulation of target mRNAs. Additionally, EVs can induce phenotypic changes due to their ability to change the recipient cell transcriptome and signaling activity [32].
Mammalian EVs are known to mediate the transportation of coding and non-coding RNAs. These significant components are protected inside the EVs and resume their function upon arrival to the host cell, imitating the mother cell. Still, EVs are enriched with mRNA and miRNA. Several non-coding RNAs have been detected, including transfer RNA (tRNAs), ribosomal RNA (rRNAs), and other types that are both a combination of coding and non-coding RNAs [33]. Extracellular RNA (exRNA) is usually enclosed by a membrane or found tightly associated with proteins [34].
The most abundant EV RNA is miRNA. The profile of the vesicle miRNA is different from their cell of origin. Indicating that miRNA is specific for EVs, and their sorting mechanism is selective. On the other hand, mRNA represents the minority of EV RNA. However, their concentration varies amongst EV types since mRNA is more abundant in MVBs than exosomes. EV mRNA can cause phenotypic changes in the receiving cells upon delivery. For example, the human telomerase reverse transcriptase gene (hTERT mRNA) can be localized into fibroblasts when transferred via EVs; upon entry, it enhances the cells’ multiplication life span, delays aging, and prevent the damage caused by DNA [35]. Another example is the presence of non-coding RNAs in glioblastoma-derived EVs; these EVs contain miR-21 that can trigger vascular endothelial growth factor signaling in human brain cells used as an angiogenic factor produced by the tumor cell. Furthermore, EVs derived from breast cancer cells enhance brain metastasis by changing the permeability of the brain [36]. EV mRNA can produce functional proteins; the active translation can occur within an hour after EV internalization [37].

3.2. Protein

The proteomic profile of EVs indicates that heat shock protein, cytoskeletal protein, transmembrane protein, and cytosolic proteins are the most abundant in EVs. Several proteins are considered markers for different types of EVs [38]. Common EV markers are listed in Table 1.
Table 1. Common EV protein cargo is often used as EV markers.

Common Markers Used for the Characterisation of EVs

Reference

Cytosolic ESCRT 1

[39]

Rabs 2

HSPA5 3, cell growth proteins (GSN 4 and FSCN1 5)

ATPase family 6 (ATP1A1, ATP1B1, and ATP2B1) signal protein (ROCK2 7, ANXA1 8, CORO1B 9, and ARF1 10)Cell communication proteins (ANXA6 11, LYN 12, OXTR 13, STX4 14, and GNB1 15)

Cation transporters

[14]

Cytoskeletal proteins (ACTG1 16, DSTN 17, FLNA 18, COTL1 19, KRT1 20, KRT9, KRT10, MSN 21, PFN1 22, and WDR1 23)

[26]

TSG101 24 and LAMP1 25

[40]

Lipid raft-associated protein (Flot1) 26

[27]

Lipid raft cellular prion protein (PrP) 27

[2]

Tetraspanin

[41]

ALIX 28 part of EVs release

[42]

VPS4B 29 and HSP70 30

[43]
1 Endosomal sorting complex required for transport, 2 Rab-associated binding, 3 Heat shock protein 5, 4 Gelsoline, 5 Fascin actin-bundling protein 1, 6 Adenosine triphosphatase protein, 7 Rho-associated kinase, 8 Annexin A1, 9 coronin actin protein, 10 ADP-ribosylation factor 1, 11 Annexin A6, 12 Lck/Yes novel tyrosine kinase, 13 oxytocin receptor, 14 Syntaxin 4, 15 Guanine nucleotide-binding protein, 16 Actin gamma 1, 17 Destrin, 18 Filamin A, 19 Coactosin-like protein 1, 20 Keratin 1,9 and 10, 21 Moesin, 22 Profilin 1, 23 DW repeat domain 1, 24 Tumor susceptibility gene 101, 25 Lysosomal-associated membrane protein 1, 26 Flotillin-1, 27 Prion protein, 28 ALG-2-interacting protein X, 29 Vacuolar protein sorting 4, 30 Heat shock protein70.
Protein is essential when EVs are being formed and released. During EV release, specific proteins are needed for membrane formation and to finish the curving and pudding of the plasma membrane; after this, protein participates in the separation process and pinching of the formed membrane. Furthermore, protein is responsible for fusing MVBs with the plasma membrane. In turn, these processes are done sequentially; they mostly require the same protein [44]. Lipids, tetraspanin, and ESCRT regulate the sorting of proteins into EVs. Other proteins packed into EVs are the results of their biogenesis process. Post-translation modifications (PTMs) similarly control the selective process of protein sorting into EVs since they regulate the protein’s function, structure, and subcellular localization [25].

3.3. EV Uptake

EV uptake can be divided into three primary levels: cellular, intracellular, or tissue. On a cellular level, EVs appear to interact with the receptors on the plasma membrane. The intracellular level uptake typically occurs via endocytosis, each cell with a specific endocytic pathway. The ability of EVs to transfer their RNA into receiving cells indicates that these vesicles prompt endogenous mechanisms for cargo delivery. Finally, an example of tissue-level uptake is EVs’ ability to cross the blood-brain barrier; these EVs facilitate the intracellular communication between neuronal cells [31].
The type of recipient cells appears to control how EVs are taken up. Most commonly, phagocytosis is the mechanism behind the cellular uptake of EVs. Moreover, the magnitude of the process depends on the recipient cell’s phagocytic capacities. On the other hand, the direct fusion of EVs with the plasma membrane can only occur in acidic conditions, such as the case in tumor cells [45]. When The endosomal/lysosomal system takes up EVs, Membrane-associated proteins also appear to be involved in EV uptake into cellular compartments [46]. On the other hand, endocytosis is the most recognized EV uptake mechanism; it is an active engulfment process that incorporates clathrin-mediated endocytosis, macropinocytosis, or phagocytosis. Still, it is not fully understood if the mechanism relies on specific EV-surface proteins or receptors [47].
Additionally, cell-specific factors can control EV uptake; this could be via direct contact, uptake, fusion, degradation, or a combination. For instance, protein interaction between EVs and host cells is a regulating factor in direct contact interaction. Furthermore, the lipids on the EVs membrane could be recognized by cells permitting non-specific uptake or fusion [46].
Some reports confirmed that a saturable transport mechanism mediates the uptake of EVs by the Caco-2 cell line. Furthermore, the protein contents of both EVs and the Caco-2 cell line affect EV uptake [48]. Additionally, these plant EVs have a therapeutic impact on cancer cells, such as the case in a study conducted by Zhang et al. [49] used the density gradient ultracentrifugation method to isolate ginger-derived EVs. A colon cancer cell line was treated with these vesicles to evaluate their uptake and therapeutic effect. The vesicles were taken up by cancer cells, and traces of plant-derived lipids were detected in the treated cell line, confirming these vesicles’ ability to transfer their cargo. Further investigations confirmed that these EVs have no toxic effect on human cells [49].
The last few years offered several EVs isolation methods that provided an excellent yield and promising quality isolates. Nevertheless, further analytical and comparative studies are needed to aid the scientists in determining their experimental approach [50]. Furthermore, the need for standard isolation, characterization, and storage guidelines is most urgent since the comparability between different studies cannot be achieved since the accuracy of the reported data are unknown [51].
The International Society for Extracellular Vesicles (ISEV) conducted a survey that invited the leaders in the field to answer questions related to EV biogenesis, cargo loading, release, and uptake by other cells. The answers were collected and vetted regarding the uptake mechanism of EVs.
It remains largely unclear how EVs interact with cells, and what dictates the next step (signaling, uptake, or fusion) of the bound EVs. The molecular drivers (e.g., proteins, lipids, sugars, nucleic acids) of EV-cell interactions are largely unknown. including how these vary among cell types, with cell state, or among EV subtypes [46].

4. Plant-Derived EVs

Human and animal EVs were the subject of research, but plant-derived EVs and their cargo are also the focus of research (Table 2). Plant extracellular vesicles demonstrated therapeutic functions via the oral route in animals. Additionally, plants are readily available, been consumed daily without any toxic effect or immune response in humans, and their assessment is the subject of many studies [52]. Plant-derived EVs were evaluated for their therapeutic activities towards tumor cells and their abilities to be used as drug carriers. These EVs were extracted from edible plants [53]. Only recently did plant-derived EVs enter the recruitment processes for clinical trials.
Table 2. Assortment of isolated plant-derived EVs and their characterization compared to mammal-derived EVs.

Plant Source

Findings

References

Ginger and carrots

The isolated EVs are similar in structure to mammal derived EVs and involved in cellular communication and plant defense response.

[49]

Leaves of Dendropanax morbifera

Similar in size to mammal EVs.

Reduces the synthesis of UV-induced melanin, therefore can be used as a natural ingredient in cosmetic products.

[13]

Arabidopsis

The EVs are saturated with a protein involved in stress and immune response in infected plant.

[54]

Watermelon

The isolated EVs are comparable to animal EVs, and the predicted function includes regulation of the development, ripening, and metabolism process of the fruit.

[55]

Curcumin

Delivery agent for a cancer drug induces a low immune response and cross mammalian parries.

[56]

Cotton

Anti-fungal activity.

[57]

Coconut, kiwi, and Hami melon

Detection of over 400 miRNA and the isolated EVs control inflammatory expression and gene-related cancer.

[58]
For example, the studied edible plants included corn, tomatoes, tobacco, sunflower, rice, and grapefruit; the latter showed an immune modulation effect in the intestine [59].
EVs derived from plant sources have a structure and cargo similar to EVs isolated from mammal cells. Furthermore, the cargo of plant EVs contains proteins, bioactive lipids, and both mRNA and microRNA, and can transfer this significant cargo to other cells, just like mammal EVs [13]. One of the research subjects was corn, tomatoes, tobacco, sunflower, rice, and grapefruit; the latter showed an immune modulation effect in the intestine. There are also clinical trials using plant EVs to prevent cancer [59]. Gut bacteria can take up plant exosomes like nanoparticles, contain RNA and siRNA in vitro, and modulate their communication with the host cells by altering their genetic makeup. These EVs, particularly their RNA, instigate tissue repair and antimicrobial immunity [60].

5. EV Function

EVs can travel long distances through the blood circulation and reach various tissues affecting the signaling process [61]. EVs can modulate several pathological and physiological functions [62]; both actions can be used as disease biomarkers, giving them a significant advantage in the biomedical field [63], including immune function and metastasis [64]; this is achieved by transporting their cargo between cells [65] (Table 3).
Table 3. Mammal-derived EVs were thoroughly investigated; their involvement in several pathological and physiological functions was recorded in various studies.

Mammal Source

Findings

References

Brain cells EVs

Play a physiological and pathological role in the CNS.

[66]

Human breast milk EVs

Contribute to the maturation process of the newborn, intestinal development, and microbial programming of infant tissue.

Modify infant immune system.

Support the cellular function and growth of the infant.

[67][68][69][70]

Bovine breast milk-derived EVs

Transport RNA to the receptor cell.

Immunoregulatory function.

[71]

Embryonic stem cells EVs

Enhanced proliferation of human tissue.

[72]

Pancreatic EVs

Stimulation of T and B cells.

[73]

Giant panda breast milk EVs

Immune system development and transfer of the genetic materials to the newborn cubs.

[74]

Zebrafish osteoblasts derived EVs

Involved in the maturation of osteoclasts.

[75]

Oviduct derived EVs

Improve the quality and development of the embryo.

[76]

Transport neurohormones to the embryo, and regulate the reactive oxygen in vitro.

[77]

Plasma-derived EVs

Healing of cardiac cells.

[37]

Astrocyte derived EVs

Neurodegeneration function.

Mesenchymal stromal cells derived EVs

Therapeutic function.

[78]

Umbilical cord-derived EVs

Immunomodulatory function.
The cargo within the EVs can interact with the receiving cell, causing them to function as mediators [79]. These vesicles cannot self-replicate [7]; their significance is presented in the RNA cargo [34].
On the other hand, EVs play a significant role in anti-inflammatory and antiapoptotic actions [80]. It could either work as protected vesicles that expel invading pathogen from the infected cell or as vector-transmitted virulence factors that will facilitate the infection [81]; for example, CNS-derived EVs illustrate defensive functions by releasing anti-inflammatory reactions [65]. In addition to its therapeutic functions, EVs released from infected cells are capable of acting similar to the mother cell, such as viruses [82], transferring viral RNA and other pathogenic proteins [83] that behave as barriers to prevent the immune mechanism from recognizing the virus. Thus, EVs have a vital role in the process of a viral infection, such as the case in malaria, and are involved in the communication between infected cells, viruses, and healthy cells [84]. Cancer cells can direct EVs as a messenger to transfer aggressive traits to the neighbor cells [63]; also, EVs can help the mobility of cancer cells, which is accomplished by forming lumps that will ensure persistence migration of the tumor [85], several studies concluded that tumor-derived EVs are part of tumor angiogenesis [86].
In the receptor cells, EVs can bind directly to the plasma membrane by activating the surface receptors of these cells or the endocytic membrane [30]; this action will instigate the release of intraluminal content in the cytoplasm of the recipient cells; this step is a significant activity that leads to the release of miRNA and mRNA [87].
Not only do mammals release EVs, a parasite, for example, Heligmosomoides polygyrus, releases EVs upon entry to the host cells that block the pro-inflammatory TNF-α and IL-6 to deliver the virulence cargo to manipulate the immune response [88]. Bacteria also release EVs essential for their survival and development; these bacterial EVs are referred to as outer membrane vesicles OMVs because they protrude from the cell’s outer membrane, 20–250 nm in size [89].

6. EVs as a Disease Biomarker and Diagnostic Tool

There is an increased interest in using EVs as disease biomarkers and liquid biopsy due to their availability in all biological fluids and the ability to transfer its cargo intact to the receptor cell. EVs as a disease biomarker have been the subject of several studies, especially cancer research [10]. EVs gained significant interest due to their relationship to pathological processes and gene delivery in short or long distances [90]. When EVs indicate dynamic changes in their content, they are directly related to the mother cell and their pathological condition, reflecting reliable disease biomarkers [91].
Furthermore, their non-invasive traits as disease biomarkers because of their miscellaneous content and their variety of biologically active components [15]. They consist of overlapping content, and their communication and functional mechanisms are not entirely different amongst all EV types. Providing a comprehensive investigation tool for some diseases, including cancer, cardiovascular diseases, neurological diseases, and infection [5]. Indicating that the detection of mutated EV-RNA is an effective tool to diagnose cancer [92].
Since cancer cells also produce EVs rich in a mitochondrial membrane protein that can be isolated from plasma that increases in melanoma, ovarian, and breast cancer [93]. There are specific features explicit for tumor-derived EVs that were the focal point of the focus of several studies as non-invasive diagnostic tools. These markers include epithelial cell adhesion molecules, epidermal growth factor receptors, and mucin [94]. EV-enriched proteins play a role in cancer development and can be used to diagnose metastatic cancer with a weak prognosis [95]. Tumor EVs are detected in almost all bodily fluids, including blood, urine, and cerebrospinal fluid. Confirms that EVs are circulating cancer biomarkers, as they represent in liquid biopsy in the breast, prostate, ovarian cancer, and melanoma [96].
The detection of EVs and their subset can predict diseases and anticipate the risk factors or development of a pathological process. Hence, EVs have also been used in a Framingham risk score (FRS) tool, a risk assessment approach [97].
The appropriate approach to use EVs in diagnosis is to study the nature of these vesicles and their origin. For example, analysis of plasma EVs confirmed their involvement with a specific type of cancer. Furthermore, some biomarkers are released directly from the cancer cell; others can be identified by their specific protein. All these indicators and tools can be incorporated with traditional tools to study cancer prognosis, development and, possible prediction [98].
For example, EVs were tested as early non-invasive diagnoses of colorectal cancer (CRC); the isolated EVs expressed tumor-specific protein circulating extracellularly, which can be utilized as early stages diagnostic tools [99]. Other than employing EVs in cancer diagnosis, some research focused on using EVs to diagnose rapidly progressed diseases that instigate a challenge for early diagnosis. Such is the case in Pleural effusion; EVs can be a promising source to detect this disease. After metabolic and lipidomic characterization of Pleural effusion-derived EVs, the results indicated that these EVs are enriched in specific metabolic cargo with a noticeable variation from tuberculosis-derived EVs and malignant tissue, indicating a promising future to use these particular characteristics as an early diagnostic tool [100].
In a study conducted by Saenz-Pipaon et al. [10] aiming to evaluate the potential use of EVs as a diagnostic tool for Peripheral Arterial Diseases PAD associated with cardiovascular conditions, the study concluded that EVs are likely reliable liquid biopsy to predict the PAD molecular component signature. Additionally, EVs play a significant role in the lungs by controlling the airways’ homeostasis and providing a significant circulating disease biomarker in chronic obstructive pulmonary disease and potential therapeutic due to its cellular communication abilities [101].
Cheng et al. [102] conducted detailed profiling of EVs collected from the frontal lope of Alzheimer’s patients. The study investigated the RNA makeup of these EVs and the changes associated with disease prognosis. The results indicated that EVs are involved in Transcriptomic deregulation of miRNA expression, achieved by horizontal transfer of the RNA via EVs. The study suggested that these early changes can be used to indicate and diagnose Alzheimer’s [102]. EVs also helps in providing long-term disease monitoring and predicting possible relapse. Moreover. A study by Melo et al. [103] acknowledged that the number of exosomes was significantly elevated in vivo in pancreatic cancer before the disease was detected by screening techniques [103].

7. Application of EVs as a Therapeutic or Drug Delivery Agent

Evidence showed that EVs function systematically as a natural response and drug delivery vehicle and can be employed for target delivery (Figure 2). EVs are detectable in most biological fluids in disease and immune response [104]. EVs can be used as original therapeutic agents or as delivery agents. Most studies focused on the possibility of using them as drug delivery cargo to a specific target due to its membrane protein [41]. Once the drug is encapsulated inside EVs, the advantage is that the drug works with the elements naturally present in them. In other cases, EVs only act as a drug carrier protecting the drug, passing it safely to the target location [105].
Figure 2. EVs are involved in several pathological and physiological processes. It can be used as a primary non-invasive diagnostic tool and, because of its role in cell communication, it can be used as a drug carrier. This figure refers to some EV functions in defense mechanisms, cellular communication, and normal physiological processes.
Several studies indicated that EVs derived from stem cells could be used as a non-invasive treatment for a brain injury or brain infection, as these EVs retain the same therapeutic functions as stem cells. Furthermore, the secretomes of stem cells, including EVs, are the active compounds that attribute to their therapeutic roles; in addition, stem cell-derived
EVs can transfer the required genetic information and protein to accomplish the therapeutic process. Several studies applied stem cell-derived EVs on injured brain cells; the EVs acted as therapeutic agents on these cells [106]. Additionally, immune cells also release EVs that act similarly to their origin and can be used in therapeutic applications. For example, dendritic cells (DC) release EVs that activate CD4+ T cells [41] via the endocrine pathway, causing enhanced cardiac performance and reducing the time needed for wound healing in myocardial infarction. EVs derived from macrophages are used in plasmin encoding therapeutic protein and vaccination [107]. Salivary EVs prevent the Zika virus attachment to the host cell, explaining why the virus is rarely transferred via saliva. However, the same study stated that the salivary EVs are not effective against SARS-CoV-2 that majorly communicate via salivary droplets [108].
There are a variety of challenges facing scientists when developing a therapeutic approach. These included toxicity, safety, target specificity, and large-scale production. Furthermore, a synthesized nanoparticle can solve the target delivery issue. However, it must undergo in vivo safety and toxicity assessment, and there is the issue with costly large-scale production. Using extracellular derived nanoparticles as drug carriers provides a possible solution since they contain lipid, RNA, and protein [49]. As EVs transfer their content from the mother cell, it is the most critical attribute in drug delivery and cell communication [109]. Their cargo, specifically RNA, was of particular interest due to the diverse population of miRNA with target genes that can influence and regulate the biological process in mammalian cells [110]. Additionally, a growing body of facts indicates that cell apoptosis proteins are involved in EV formation. Unveiling the interaction pathway between EVs and autophagy that promotes cancer cell motility, providing significant advantages in early diagnosis and cancer treatment using EVs [111]. The protein profile of EVs derived from mesenchymal cells retains a therapeutic effect observed in vivo. These proteins include osteoprotegerin and angiogenin [112].
Drug loading into EVs can be divided into two strategies. The first is directly loading the drug into the exosomes; the second is targeting the mother cell by loading drugs during the biogenesis of exosomes [113]. Furthermore, in the case of loading lipophilic drugs, the process is relatively easy due to the interaction between EVs lipid bilayer and the drug, which occurs via hydrophobic interaction [114]. Several methods were utilized to achieve exogenous loading of EVs with drugs, including electroporation, incubation, sonication, and thawing. The level of success differs from one method to another; some cause degradation to either EVs or their cargo [115].
The first time EVs were used as a drug cargo was when San et al. [116] used EV-encapsulated curcumin fused with the plasma membrane. It was reported that EVs isolated from the plasma of humans and rats showed a protective mechanism against Acute myocardial ischemia/reperfusion [117]. Successfully, EVs were loaded with anti-cancer and RNA-based drugs and cancer vaccination. These applications are based on cancer immunotherapy, indicating that the success of this approach is that EVs can be taken up efficiently by macrophages and tumor cells [118]. Other drugs loaded into EVs include a lipophilic drug with a small molecular weight and RNA-based drugs, for example, small interfering RNA (siRNA) [114]. Furthermore, the blood-brain barrier is the most selective in the human body. There are three primary methods to deliver drugs and therapeutic components into the brain, including invasive, pharmacological, and physiological approaches—the first approach is based on delivering drugs by breaching the blood-brain barrier. The pharmacological method includes modifying the active compound to enter the brain via a passive crossing. The last approach is the most efficient; it depends on the naturally present receptors found in abundance on the surface of the blood–brain barrier. These receptors provide easy and equal distribution of the loaded drugs into the brain. EVs possess two significant advantages as the usage will be non-invasive and were proven to cross the blood-brain barrier easily [119].
Employing EVs as a drug carrier has several advantages compared to platelets. To mention a few, (1) EVs are smaller in size, which is an advantage when delivering drugs to cancer cells. For instance, EVs were more efficient in delivering the membrane protein SIRPa than ferritin. (2) EVs are originated from different sources. They are smaller and less toxic than lysosomes, with enhanced tissue biocompatibility and tolerance. (3) The cargo within EVs is protected by the double lipid layer that reduces the degradation and improves their biological stability. (4) Target cells can exclusively distinguish the specific receptors present on the EV membrane, reducing systemic toxicity and lowering drug outflow compared to conventional drug administration methods. (5) It is established that EVs could pass the BBB, giving an advantage in treating brain tumors. (6) Due to EVs’ ability to circulate the blood, the drug’s effect can last longer in the system [53].

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Nada Basheir Ali , Ahmad Faizal Abdull Razis , Der Jiun Ooi , Kim Wei Chan , Norsharina Ismail , Jhi Biau Foo
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