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Review

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

by
Yasunari Matsuzaka
1,2,* and
Ryu Yashiro
2,3
1
Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku 108-8639, Tokyo, Japan
2
Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8551, Tokyo, Japan
3
Department of Infectious Diseases, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi 181-8611, Tokyo, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(21), 12971; https://doi.org/10.3390/ijms232112971
Submission received: 10 August 2022 / Revised: 7 October 2022 / Accepted: 21 October 2022 / Published: 26 October 2022

Abstract

:
Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by delivering their contents, such as nucleic acids, proteins, and lipids, to distant target cells. EVs play a role in the progression of several diseases. In particular, programmed death-ligand 1 (PD-L1) levels in exosomes are associated with cancer progression. Furthermore, exosomes are being used for new drug-delivery systems by modifying their membrane peptides to promote their intracellular transduction via micropinocytosis. In this review, we aim to show that an efficient drug-delivery system and a useful therapeutic strategy can be established by controlling the molecular docking and intracellular translocation of exosomes. We summarise the mechanisms of molecular docking of exosomes, the biological effects of exosomes transmitted into target cells, and the current state of exosomes as drug delivery systems.

1. Introduction

Intracellular communication mediated via extracellular vesicles (EVs) and drug-delivery systems based on EV biology have emerged as areas of investigation with a significant potential to impact human health [1,2,3,4]. EVs are comprised of lipid bilayer membranes and are classified into exosomes, microvesicles, and apoptotic bodies, mainly based on differences in their biogenesis [5,6,7,8]. Microvesicles emerge from the plasma membrane of the cell and have diameters of approximately 100 nm to 1000 nm [9,10]. Apoptotic bodies are giant vesicles formed from the plasma membrane during the induction of apoptosis and are approximately 1–5 μm in diameter [11,12,13]. Exosomes are formed within the intracellular multivesicular endosome (MVE) and are approximately 30–150 nm in diameter [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. EVs are secreted by almost all cells. The release of the exosomes into the extracellular space is mediated by the fusion of the MVE membrane with the plasma membrane. Exosomes are found in various body fluids, such as plasma, serum, urine, saliva, and breast milk, and are also released in the culture supernatants of many cell lines [31,32,33,34]. They contain functional molecules, such as nucleic acids, microRNAs (miRNAs), messenger RNA (mRNA), and circulating RNA (circRNAs); metabolites and lipids on their membrane, such as phosphatidylserine; proteins, such as enzymes; and are characterized by some antigens, such as CD9, CD63, and CD81 [35,36,37,38,39,40,41,42,43,44,45,46,47]. These molecules are important for the characterisation of the cell type of origin for a given population of exosomes [48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95]. Secreted vesicles are transported by body fluids, such as blood, to cells where their impact is likely to be the greatest. The release of vesicles mediates intercellular communication [48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84]. In summary, exosomes reflect the characteristics of the cell from which they were derived, are taken up by other cells, and are responsible for the intercellular transmission of information. In this review, we aim to summarise the intercellular mechanisms of exosomes, the biological effects of exosomes transmitted into target cells, and the current state of exosomes as drug-delivery systems. In addition, we summarize the latest studies on EVs as novel drug-delivery systems and their effects on cancer.

2. EVs in Cancer Metastasis and Malignant Transformation

EV-mediated intracellular communication plays a role not only in maintaining cell homeostasis, but also in disease progression [96,97,98,99]. Exosomes are associated with several diseases, including cancer metastasis, which is the invasion and spread of primary cancer cells into other organs [100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]. Exosomes have been shown to play an important role in the formation of the cancer microenvironment and the mechanisms of cancer malignancy, such as cancer cell growth, infiltration, metastasis, and pre-metastasis niche [132,133,134,135,136,137,138,139,140]. Tumour-derived miRNA exosomes have been shown to affect tumour cells and stromal cells of the tumour microenvironment, such as fibroblasts and macrophages [141,142,143,144,145]. For example, miRNA exosomes secreted by cancer cells induce intratumoural angiogenesis, thereby promoting metastasis [145,146,147,148,149]. Moreover, miR-181c promotes the delocalization of actin fibres by downregulating the 3-phosphoinositide-dependent protein kinase 1 (PDPK1) gene [150].
Cancer-derived exosomes disrupt the blood–brain barrier and promote brain metastasis [151,152,153,154]. In breast cancer, tumour-derived exosomes containing miR-181c have been shown to promote cancer metastasis to the brain by disrupting the blood–brain barrier [150]. In addition, exosomes secreted by ovarian cancer containing matrix metallopeptidase 1 (MMP1) mRNAs induce peritoneal mesothelial cells to undergo apoptotic cell death, thereby promoting peritoneal cancer metastasis [155].

3. EV-Mediated Immune Escape of Cancer Cells

Tumours evade the immune systems by secreting exosomes containing proteins that suppress the immune response. A new pathway for such immune evasion has been identified in a laboratory model of skin cancer melanoma and patients suffering from the disease. Tumour cells release exosomes coated with programmed death-ligand 1 (PD-L1) proteins, which are immune checkpoint proteins that bind to immune cells to inactivate them [156,157,158,159,160,161,162,163]. This prevents immune cells from reaching tumour cells and attacking them. [164,165,166,167,168,169,170,171,172,173,174,175,176,177,178]. PD-L1 is present in exosomes released from melanoma cells [178,179,180,181,182,183,184,185,186]; however, exosomes derived from metastasised melanoma cells have a higher PD-L1 content than those derived from primary focal melanoma cells. Moreover, an electron microscope analysis revealed the PD-L1 protein was carried on the surface of the protein [187]. This suggests that PD-L1 on the surface of exosomes interacts directly with the immune cells. Furthermore, PDL1-positive exosomes mainly bind to cytotoxic T cells, preventing their proliferation and attack on cancer cells [159,188]. In a mouse model of melanoma that closely mimics human cancer, the injection of PDL-1-coated exosomes promoted tumour growth and reduced the number of T cells and other immune cells in and around the tumour (Figure 1) [162,173,189,190,191,192]. In addition, exosomes carrying PD-L1 have been identified in blood samples of patients with a history of breast cancer, melanoma, or lung cancer who had received treatments for their respective diseases [193,194,195].
Melanoma elicits a particularly strong immune response, and multiple immune checkpoint inhibitors have been approved by the US Food and Drug Administration for the treatment of melanoma [163,164,165,166,167,168,169,170]. Interestingly, based on PD-L1 levels in exosomes, patients who are most likely to respond to checkpoint inhibitors can be identified and the response to these drugs can be evaluated [162,194,196,197,198,199]. For example, compared to patients with high exosomal PD-L1 levels before treatment, those with lower levels responded remarkably better to treatments with the checkpoint inhibitor pembrolizumab (Keytruda), which can block PD-1, the immune cell binding partner of PD-L1 [185,196,198,200,201,202,203,204,205]. In contrast, after the start of treatment, higher exosomal PD-L1 levels reflected a reduction in tumour size [206,207,208], indicating that two different mechanisms occur. Before treatment, exosomal PD-L1 levels likely reflect the size of the tumour and the extent of the disease. In other words, a high blood PD-L1 level indicates the presence of several tumours and is associated with a poor prognosis. After treatment, a rapid increase in exosomal PD-L1 in patients who responded to treatment indicates that T cells are activated and secrete more cytokines, such as interferon-γ (IFN-γ), which are signalling molecules that can stimulate the immune system [162,191,209,210,211]. In melanoma cell lines, treatment with IFN-γ-has been shown to increase exosomal PD-L1 [162,212]. Moreover, analysis of patient samples revealed that exosomal PD-L1 levels tended to increase or decrease with increasing IFN-γ levels. Therefore, these findings also indicate that levels of exosomal PD-L1 in blood may help in selecting the appropriate treatment for different individuals. However, the exact mechanism by which exosomes carrying PD-L1 affect the immune response to tumours in patients with melanoma remains uncertain. Moreover, other types of immunomodulatory molecules may be present on the surface of these exosomes. Therefore, further research is needed using more samples from patients with melanoma and other cancer types and close comparison of PD-L1 in tumour biopsies with exosomes released from tumours should be observed. For example, approximately 40% of human melanoma cells express significant amounts of PD-L1 on their surfaces [213]. The presence of large amounts of exosomal PD-L1 in the blood of melanoma patients also suggests that PDL-1 has an overall effect on immunosuppression in those patients [161,162,182,186,214]. However, presently, there is no evidence that the immunity of patients with stage 4 melanoma is impaired.
For many years, exosomes have been thought to only function as molecular carriers that carry waste from cells; however, it has become clear that EVs affect various biological processes and diseases, including immune responses and cancer [215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232]. Nonetheless, it is difficult to identify these exosomes. Moreover, the capacity of each exosome is only one-millionth of that of a typical cell, and most modern biomedical research tools are not suitable for the accurate and functional analysis of cargos within individual exosomes. Therefore, new tools and approaches would be useful to study these small vesicles in more detail.

4. Intracellular Translocation of Nucleic Acids and Proteins via EVs

EVs are highly expected to be next-generation drug carriers for the following reasons: (1) possible immunoregulation, (2) possible expression of membrane proteins by genetic engineering, (3) intracellular communication pathways, (4) low cytotoxicity, and (5) infinite secretion [1,233,234,235,236,237,238,239,240,241]. For example, small interfering RNA (siRNA) delivery for a BACE (β-site of Amyloid Precursor Protein cleaving enzyme) target using exosomes has proven to be beneficial in the treatment of Alzheimer’s disease [242,243,244]. Furthermore, because exosomes that have miRNAs and enzyme-encapsulating cocktails, which have functions such as cell proliferation suppression and cell migration promotion, are naturally secreted from cells, they are highly expected to be used as drugs for treating several diseases [245,246,247,248,249,250,251,252]. The macropinocytosis pathway is important for the intracellular translocation of exosomes [253,254,255,256,257,258]. Therefore, by modifying the membrane surface of exosomes with a functional peptide to induce macropinocytosis, it is possible to considerably increase the efficiency of the intracellular delivery of exosomes [254,255,257].

5. EV Uptake in Target Cells via Macropinocytosis

Eukaryotic cells take up molecules, such as extracellular proteins and lipoproteins, by a process called endocytosis, which includes clathrin-dependent or -independent endocytosis and micropinocytosis (Figure 2) [259,260,261,262,263,264,265,266,267,268,269]. In clathrin-dependent endocytosis, when a ligand molecule binds to a receptor on the plasma membrane, a clathrin molecule binds to the cytosol via an AP2 adaptor protein, and a ball-shaped structure of the plasma membrane is formed [270,271,272,273].
In addition, dynamin then separates the endosome from the plasma membrane via clathrin-dependent endocytosis [274,275,276]. These formed endosomes usually measure up to approximately 120 nm in diameter because clathrin limits the size of endosomes [277,278,279] Therefore, in normal clathrin-dependent endocytosis, the intracellular translocation of EVs is inefficient. By contrast, macropinocytosis can take up extracellular molecules with a diameter greater than 1 mm, including nutrients, into cells. Macropinocytosis is a clathrin-independent pathway, characterised by actin-dependent reorganisations (lamellipodia) of the plasma membrane to form macropinosomes [280]. Macropinocytosis is induced by the activation of various receptors, such as the epidermal growth factor receptor (EGFR), which is highly expressed in tumour cells, such as human epidermal cancer A431 and the chemokine receptor CXCR4 [253,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297].
Furthermore, in vitro experiments have revealed that human pancreatic cancer-derived MIA PaCa cells, which highly induce macropinocytosis, have high exosomal migration efficiency [253,298,299]. Normally, the exosome membrane is negatively charged (zeta potential is approximately −10 mV); therefore, it repels with the negatively charged plasma membrane [300,301,302,303]. However, in the macropinocytosis pathway, exosomes that do not easily interact with the plasma membrane can be effectively wrapped and incorporated into cells using ruffling [296,304]. These findings highly suggest that macropinocytosis contributes to intercellular communication.
In pancreatic cancer, exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRAS, which is a common mutation in pancreatic cancer. These exosomes were effectively taken up by target cells by macropinocytosis and exerted a remarkable effect in suppressing pancreatic cancer cell growth in vivo [281,305,306,307,308]. Moreover, in lung cancer, gefitinib (Iressa), an anticancer drug that inhibits the epidermal growth factor receptor (EGFR), was shown to increase the intracellular translocation of exosomes, but decrease that of liposomes, which are typically used for drug-delivery systems [309]. In addition, compared to liposome-encapsulated doxorubicin, exosome-encapsulated doxorubicin results in robustly higher anticancer activity against non-small cell lung cancer [310,311]. Furthermore, degradation of the exosomal membrane proteins further enhanced intracellular migration induced by gefitinib treatment [304]; thus, exosomal membrane lipids may contribute to the promotion of intracellular translocation during gefitinib treatment. Additionally, a macropinocytosis inhibitor was shown to remarkably suppress the growth of pancreatic cancer cells both in vitro and in vivo [288,289,290,291,292]. Thus, macropinocytosis pathway inhibitors can be used to suppress the progression of pancreatic cancer. These findings suggest that drug applications from a new perspective are highly beneficial to treat cancer.

6. Techniques for Functional Peptide Modifications on the Exosomal Membrane

A previous study on the intracellular uptake of exosomes using a functional peptide modification technique on the exosomal membrane has revealed its importance for the intracellular translocation of exosomes [258,298,312]. Two simple techniques for binding peptides to the exosomal membrane without modifying the components of the membrane have been reported: (1) acylating a peptide such as a stearyl group and (2) using a peptide with a linker including a succinimide group [298,313]. In the method of acylating a peptide with a stearyl group, when the peptide is synthesised on beads by the Fmoc solid phase method, the N-terminal is dehydrated and condensed with stearic acid, and then deprotected and purified to obtain the acylated target peptide [254,258,314]. For example, a peptide with a stearyl group can easily be inserted into an exosomal membrane with an acylated hydrophobic part, and the peptide can be presented on the exosomal membrane simply by mixing the peptide with the exosome in a solution [258,315]. Peptides that are not present in the exosome membrane can be removed by ultrafiltration. This method does not require consideration of the sequence of the peptide; however, for highly hydrophobic peptides, the solubility may deteriorate owing to the addition of a hydrophobic group to the peptide. In such cases, the balance between the control of the hydrophobic group to be acylated and the degree of insertion into the exosome membrane should be considered. Furthermore, in the method using a peptide with a linker including a succinimide group, it is possible to covalently bind the target peptide and the exosomal membrane protein using a divalent linker, such as N-(6-maleimidocaproyloxy) sulphosuccinimide and sodium salt (sulpho-EMCS) [257]. During peptide synthesis, after introducing cysteine residues into the peptide sequence, an acetylation cap with acetic anhydride is applied at the N-terminal cysteine residue side chain of the purified target, and the maleimide group of EMCS is bound by Michael addition and purified again. Next, by mixing the purified peptide and exosome, the succinimide group possessed by the linker of the peptide reacts with the membrane protein amino group of the exosome, and the target peptide and exosome are covalently attached. This method can be used when an amino group, such as lysine or a cysteine residue, does not exist in the peptide sequence to be originally bound. However, it may be necessary to introduce an unnatural amino acid into the amino acid sequence and use a linker bond using click chemistry. When the first method is used, the membrane protein of the exosome is hardly affected and the peptide can be modified, whereas in the second method, since a covalent bond is formed on the side chain of the constituent amino acids of the membrane protein, the original function of the membrane protein may be affected. However, because the second method modifies the peptide by covalent bonding, peptide retention on the exosomal membrane is higher than that of the anchor type inserted into the membrane using the first method. Therefore, it is evident that the macropinocytosis pathway is important for the intracellular translocation of exosomes [253]. The development of a technique that can induce macropinocytosis using exosomes can enhance intracellular migration.
A membrane-permeable arginine peptide-modified exosome that induces macropinocytosis has been developed. In addition, the human immunodeficiency virus (HIV)-1 encodes the transcription factor trans-activator of transcription (Tat) protein-derived peptides and oligoarginines, which are cell-penetrating peptides that can easily penetrate cells (CPPs) [316]. CPPs contain many arginine residues in their sequence; therefore, they accumulate in the plasma membrane because of their interactions with heparan sulphate of the sugar chain of proteoglycan in the membrane. As a result, clustering of proteoglycan (syndecan-4), intracellular binding of protein kinase C, alpha (PKCα) to proteoglycan, and signal transduction occur. Moreover, EVs can be efficiently taken up into cells by the activation of the small G protein Rac1, which induces macropinocytosis due to the remodelling of the actin skeleton [316]. Therefore, exosomes induce macropinocytosis in target cells by binding to membrane-permeable arginine peptides. Moreover, the EV uptake efficiency depends on the number of peptides bound to the exosome membrane. When octaarginine (stearyl-R8), which is a typical membrane-permeable arginine peptide with the previously mentioned stearyl group at the N-terminus, is mixed with CD63-GFP (green fluorescent protein)-exosomes to modify the peptide on the exosome, exosomes can act as scaffolds to promote the clustering of syndecan-4 on the plasma membrane of target cells and induce macropinocytosis with foliate pseudopodia by modifying stearyl-R8. This can remarkably increase the efficiency of the intracellular translocation of exosomes. Notably, this method caused almost no cytotoxicity [258].
In addition, the clustering of proteoglycans by the peptide and the induction of macropinocytosis are affected by the number of arginine residues in the sequence [316,317]. Furthermore, the binding of oligoarginines with different numbers of arginine residues to the membrane surface of CD63-GFP-exosome does not affect the morphology of the exosomes. Notably, this method did not exhibit cytotoxic effects. In addition, as previously mentioned, despite the negative charge of the exosomal membrane, when oligoarginine and exosomes were simply mixed without using a divalent linker, no increase in the efficiency of intracellular translocation of exosomes was observed with any oligoarginine [257]. Thus, the strong binding of a functional peptide to the exosomal membrane using the method previously discussed is important for fully exploiting the functionality of the peptide. It was also reported that the activity of drug-encapsulated exosomes was markedly higher in exosomes bound with the R16 peptide, which has a relatively low intracellular translocation compared with those bound to R8 and R12 peptides, which have a higher translocation. This suggests that the cytosolic release efficiency of modified exosomes after intracellular translocation is high, although R16 peptides have lower intracellular translocation than the R8 and R12 peptides [257]. Therefore, when selecting a functional peptide, a well-balanced peptide must be selected by considering not only the intracellular transfer efficiency, but also the release efficiency after intracellular transfer.
Normally, when the drug is delivered intracellularly by endocytosis or macropinocytosis, the contents of the endosome are degraded by various enzymes [318,319]. Therefore, the drug must escape into the cytosol before lysosomal degradation. Nakase et al. have developed an efficient cytosolic delivery technique for proteins using the GALA peptide, which is a pH-sensitive membrane fusion peptide [320,321]. The GALA peptide (amino acid sequence: WEAALAEALAEALAEHLAEALAEALEALAA) is an artificial peptide that mimics the membrane fusion protein of a virus composed of 30-residue amino acids. When the pH is neutral, the peptide has almost no secondary structure; however, as the pH decreases, the helix content increases, facilitating the incorporation of the peptide into the membrane, which promotes membrane destabilisation and fusion [320,321]. This GALA peptide is rich in glutamate residues and negatively charged. However, since the cell plasma membrane is also negatively charged, the intracellular transferability of the GALA peptide alone is extremely low. Therefore, the formation of a complex between a cationic lipid and GALA significantly increased the intracellular translocation of the GALA peptide. Furthermore, by binding molecules, such as proteins to be carried to the cytosol, to the GALA peptide and forming a complex with the cationic lipid, this complex is taken up into cells by endocytosis, and the target molecule bound to the GALA peptide can be effectively released into the cytosol [321,322]. Although the use of a large number of cationic lipids causes cytotoxicity, cells hardly uptake GALA even if they uptake exosomes; therefore, complex formation using lipids is important. Furthermore, when ammonium chloride was used to suppress the decrease in pH in endosomes, the cytosolic escape effect of the GALA peptide was markedly reduced. This finding indicates that endosome maturation is important for peptide function. In addition, it is important to optimise the concentration in complex formation because the difference in the concentration of the GALA peptide affects complex formation and cytosol escape efficiency. This epoch-making method can easily promote the cytosolic release of exosome-encapsulated molecules by simply mixing them with exosomes. Therefore, it can be applied to various drug-encapsulating exosomes (including miRNAs) in the future, such as miRNA-encapsulating exosomes in myocytes [323].

7. Storages of EVs as a Long-Term Strategy

It is important to establish a preservation method for drug-encapsulating exosomes. Exosomes can be stored in a refrigerator for approximately 1–2 weeks at the most but can be frozen for several months. However, repeated freezing and thawing are known to have a serious effect on the morphology of exosomes. For preservation methods, such as freeze-drying exosomes bound to R16 peptide and then adding water to restore them, the R16 peptide-modified exosomes were shown to be hardly affected [260]. In contrast, for R16-bound exosomes containing drugs, as described above, freeze-drying resulted in a considerable reduction in drug activity. Therefore, the efficiency of the cytosolic release of the encapsulated drug after intracellular transfer may be reduced after lyophilisation. The storage capacity of EVs can depend on their number, size, function, temperature, duration, and freeze–thaw cycles [324,325,326,327,328,329].

8. Clinical Application

EVs are attracting attention as drug carriers that deliver nucleic acid medicine, which is a general term for medicines that do not directly encode proteins, but directly act on DNA, RNA, or chemically synthesized oligonucleotides on proteins, to the affected area [330,331,332,333,334,335]. Types of nucleic acid drugs include antisense nucleic acids, siRNA, miRNA, decoy nucleic acids, nucleic acid aptamers, etc. These are attracting attention as new therapeutic agents following low molecular weight drugs and antibody drugs that have already been clinically applied. On the other hand, nucleic acid drugs are easily degraded in blood, which contains many digestive enzymes. Therefore, in order to obtain clinical efficacy against various diseases through blood, a drug carrier that is safe to the body, prevents degradation by digestive enzymes, and selectively delivers nucleic acid medicines to the affected area is required. EVs are stable in blood due to a lipid bilayer membrane. They are about 100 nm in size, and renal excretion, immune mechanism, and enhanced permeation and retention effect are optimal. EVs are secreted by various cells in the body, and compared to artificially constructed drug carriers, immune reactions are less likely to occur. Clinical trials of EVs have already been conducted and their safety has been investigated. It is suggested that EVs are transported in an organ-specific manner. In fact, many researchers have already begun to report on in vivo studies in which nucleic acid drugs, such as siRNA, are encapsulated in EVs [336,337,338,339,340]. Furthermore, treatment methods targeting EVs are being investigated, and some are already undergoing clinical trials. The main therapeutic strategies are roughly divided into two: one is a method of targeting and removing/inhibiting harmful EVs themselves, and the other is a method of utilizing beneficial EVs. The former is thought to inhibit EVs secretion, remove EVs present in the blood, and inhibit EVs uptake. Further, Nishida-Aoki et al. reported that the EVs removal by tail vein administration of antibodies to xenograft mouse models using human cancer cell lines can suppress cancer metastasis [341]. These results suggest that EVs-targeted therapy may have clinical efficacy. The latter mainly includes the use of EVs loaded with antigenic peptides as vaccines and the use of mesenchymal stem cell (MSC)-derived EVs. In particular, MSC-derived EVs have already been clinically tested for steroid-refractory graft-versus-host disease, and there have been reports of significant improvement in symptoms without obvious adverse effects [342,343,344].

9. Conclusions

The intracellular transduction of exosomes, including miRNAs and proteins, is regulated by clathrin-dependent or -independent endocytosis and micropinocytosis. By controlling the organ or tissue tropism of exosomes and promoting their intracellular translocation, we expect to construct safe and effective drug delivery systems. Moreover, modification of the peptides on the surface of the exosomes is a novel technique to generate drug-encapsulating exosomes. Furthermore, modified exosomes whose surfaces are modified with binding ligands can be expected to be highly safe and result in effective transduction of DDS by controlling tissue tropism in vivo. Thus, it is expected to become a touchstone for the establishment of new treatment strategies for various diseases, including cancer, especially for intractable diseases for which no treatment methods have been available thus far.

Author Contributions

Writing, review, and editing, Y.M.; supervision, R.Y.; funding acquisition, Y.M. All authors have read and agreed to the published version of the manuscript.

Funding

This review was funded by the Fukuda Foundation for Medical Technology, and APC was funded by the Fukuda Foundation for Medical Technology.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Matsuzaka, Y.; Yashiro, R. Extracellular Vesicles as Novel Drug-Delivery Systems through Intracellular Communications. Membranes 2022, 12, 550. [Google Scholar] [CrossRef] [PubMed]
  2. Giovannelli, P.; Di Donato, M.; Galasso, G.; Monaco, A.; Licitra, F.; Perillo, B.; Migliaccio, A.; Castoria, G. Communication between cells: Exosomes as a delivery system in prostate cancer. Cell Commun. Signal. 2021, 19, 110. [Google Scholar] [CrossRef]
  3. Choi, H.; Choi, Y.; Yim, H.Y.; Mirzaaghasi, A.; Yoo, J.K.; Choi, C. Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes. Tissue Eng. Regen. Med. 2021, 18, 499–511. [Google Scholar] [CrossRef]
  4. Gaurav, I.; Thakur, A.; Iyaswamy, A.; Wang, X.; Chen, X.; Yang, Z. Factors Affecting Extracellular Vesicles Based Drug Delivery Systems. Molecules 2021, 26, 1544. [Google Scholar] [CrossRef] [PubMed]
  5. Qin, X.; Zhou, Y.; Jia, C.; Chao, Z.; Qin, H.; Liang, J.; Liu, X.; Liu, Z.; Sun, T.; Yuan, Y.; et al. Caspase-1-mediated extracellular vesicles derived from pyroptotic alveolar macrophages promote inflammation in acute lung injury. Int. J. Biol. Sci. 2022, 18, 1521–1538. [Google Scholar] [CrossRef] [PubMed]
  6. Tayebi, M.; Yang, D.; Collins, D.J.; Ai, Y. Deterministic Sorting of Submicrometer Particles and Extracellular Vesicles Using a Combined Electric and Acoustic Field. Nano Lett. 2021, 21, 6835–6842. [Google Scholar] [CrossRef] [PubMed]
  7. Nishimura, T.; Oyama, T.; Hu, H.T.; Fujioka, T.; Hanawa-Suetsugu, K.; Ikeda, K.; Yamada, S.; Kawana, H.; Saigusa, D.; Ikeda, H.K.; et al. Filopodium-derived vesicles produced by MIM enhance the migration of recipient cells. Dev. Cell 2021, 56, 842–859.e8. [Google Scholar] [CrossRef]
  8. Liu, T.; Hooda, J.; Atkinson, J.M.; Whiteside, T.L.; Oesterreich, S.; Lee, A.V. Exosomes in Breast Cancer—Mechanisms of Action and Clinical Potential. Mol. Cancer Res. 2021, 19, 935–945. [Google Scholar] [CrossRef] [PubMed]
  9. Lazar, S.; Goldfinger, L.E. Platelets and extracellular vesicles and their cross talk with cancer. Blood 2021, 137, 3192–3200. [Google Scholar] [CrossRef]
  10. Menck, K.; Sivaloganathan, S.; Bleckmann, A.; Binder, C. Microvesicles in Cancer: Small Size, Large Potential. Int. J. Mol Sci. 2020, 21, 5373. [Google Scholar] [CrossRef]
  11. Wang, C.; Liu, J.; Yan, Y.; Tan, Y. Role of Exosomes in Chronic Liver Disease Development and Their Potential Clinical Applications. J. Immunol. Res. 2022, 2022, 1695802. [Google Scholar] [CrossRef] [PubMed]
  12. Shang, X.; Fang, Y.; Xin, W.; You, H. The Application of Extracellular Vesicles Mediated miRNAs in Osteoarthritis: Current Knowledge and Perspective. J. Inflamm. Res. 2022, 15, 2583–2599. [Google Scholar] [CrossRef]
  13. Fu, Y.; Sui, B.; Xiang, L.; Yan, X.; Wu, D.; Shi, S.; Hu, X. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis. 2021, 12, 596. [Google Scholar] [CrossRef] [PubMed]
  14. Xiong, Y.; Song, J.; Huang, X.; Pan, Z.; Goldbrunner, R.; Stavrinou, L.; Lin, S.; Hu, W.; Zheng, F.; Stavrinou, P. Exosomes Derived from Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke. Front. Neurosci. 2022, 16, 899887. [Google Scholar] [CrossRef]
  15. Xu, Y.; Hu, Y.; Xu, S.; Liu, F.; Gao, Y. Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations. Front. Neurol. 2022, 12, 747380. [Google Scholar] [CrossRef] [PubMed]
  16. Bischoff, J.P.; Schulz, A.; Morrison, H. The role of exosomes in intercellular and inter-organ communication of the peripheral nervous system. FEBS Lett. 2022, 596, 655–664. [Google Scholar] [CrossRef]
  17. Chen, Y.; Zhao, Y.; Yin, Y.; Jia, X.; Mao, L. Mechanism of cargo sorting into small extracellular vesicles. Bioengineered 2021, 12, 8186–8201. [Google Scholar] [CrossRef] [PubMed]
  18. Waldenmaier, M.; Seibold, T.; Seufferlein, T.; Eiseler, T. Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication. Cancers 2021, 13, 4844. [Google Scholar] [CrossRef] [PubMed]
  19. Kaur, S.; Verma, H.; Dhiman, M.; Tell, G.; Gigli, G.L.; Janes, F.; Mantha, A.K. Brain Exosomes: Friend or Foe in Alzheimer’s Disease? Mol. Neurobiol. 2021, 58, 6610–6624. [Google Scholar] [CrossRef] [PubMed]
  20. Liu, J.; Ren, L.; Li, S.; Li, W.; Zheng, X.; Yang, Y.; Fu, W.; Yi, J.; Wang, J.; Du, G. The biology, function, and applications of exosomes in cancer. Acta Pharm. Sin. B 2021, 11, 2783–2797. [Google Scholar] [CrossRef]
  21. Yang, Y.; Yuan, L.; Du, X.; Zhou, K.; Qin, L.; Wang, L.; Yang, M.; Wu, M.; Zheng, Z.; Xiang, Y.; et al. Involvement of epithelia-derived exosomes in chronic respiratory diseases. Biomed. Pharmacother 2021, 143, 112189. [Google Scholar] [CrossRef]
  22. U Stotz, H.; Brotherton, D.; Inal, J. Communication is key: Extracellular vesicles as mediators of infection and defence during host-microbe interactions in animals and plants. FEMS Microbiol. Rev. 2022, 46, fuab044. [Google Scholar] [CrossRef]
  23. Hade, M.D.; Suire, C.N.; Suo, Z. Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine. Cells 2021, 10, 1959. [Google Scholar] [CrossRef] [PubMed]
  24. Thej, C.; Kishore, R. Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration. Cells 2021, 10, 1811. [Google Scholar] [CrossRef]
  25. Whiteside, T.L.; Diergaarde, B.; Hong, C.S. Tumor-Derived Exosomes (TEX) and Their Role in Immuno-Oncology. Int. J. Mol. Sci. 2021, 22, 6234. [Google Scholar] [CrossRef] [PubMed]
  26. Gurunathan, S.; Kang, M.H.; Kim, J.H. A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes. Int. J. Nanomed. 2021, 16, 1281–1312. [Google Scholar] [CrossRef]
  27. Rezaie, J.; Aslan, C.; Ahmadi, M.; Zolbanin, N.M.; Kashanchi, F.; Jafari, R. The versatile role of exosomes in human retroviral infections: From immunopathogenesis to clinical application. Cell Biosci. 2021, 11, 19. [Google Scholar] [CrossRef] [PubMed]
  28. Koohsarian, P.; Talebi, A.; Rahnama, M.A.; Zomorrod, M.S.; Kaviani, S.; Jalili, A. Reviewing the role of cardiac exosomes in myocardial repair at a glance. Cell Biol. Int. 2021, 45, 1352–1363. [Google Scholar] [CrossRef] [PubMed]
  29. Murugesan, S.; Saravanakumar, L.; Powell, M.F.; Rajasekaran, N.S.; Kannappan, R.; Berkowitz, D.E. Role of exosomal microRNA signatures: An emerging factor in preeclampsia-mediated cardiovascular disease. Placenta 2021, 103, 226–231. [Google Scholar] [CrossRef] [PubMed]
  30. Kita, S.; Shimomura, I. Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes. J. Biochem. 2021, 169, 173–179. [Google Scholar] [CrossRef] [PubMed]
  31. Jayaseelan, V.P. Emerging role of exosomes as promising diagnostic tool for cancer. Cancer Gene Ther. 2020, 27, 395–398. [Google Scholar] [CrossRef] [PubMed]
  32. Hesari, A.; Golrokh Moghadam, S.A.; Siasi, A.; Rahmani, M.; Behboodi, N.; Rastgar-Moghadam, A.; Ferns, G.A.; Ghasemi, F.; Avan, A. Tumor-derived exosomes: Potential biomarker or therapeutic target in breast cancer? J. Cell Biochem. 2018, 119, 4236–4240. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Li, S.R.; Man, Q.W.; Gao, X.; Lin, H.; Wang, J.; Su, F.C.; Wang, H.Q.; Bu, L.L.; Liu, B.; Chen, G. Tissue-derived extracellular vesicles in cancers and non-cancer diseases: Present and future. J. Extracell. Vesicles 2021, 10, e12175. [Google Scholar] [CrossRef] [PubMed]
  34. Jin, C.; Wu, P.; Li, L.; Xu, W.; Qian, H. Exosomes: Emerging Therapy Delivery Tools and Biomarkers for Kidney Diseases. Stem Cells Int. 2021, 2021, 7844455. [Google Scholar] [CrossRef] [PubMed]
  35. Wang, J.; Wang, J.; Li, X.; Shu, K. Cell-Derived Exosomes as Therapeutic Strategies and Exosome-Derived microRNAs as Biomarkers for Traumatic Brain Injury. J. Clin. Med. 2022, 11, 3223. [Google Scholar] [CrossRef] [PubMed]
  36. Mousavi, S.M.; Amin Mahdian, S.M.; Ebrahimi, M.S.; Taghizadieh, M.; Vosough, M.; Sadri Nahand, J.; Hosseindoost, S.; Vousooghi, N.; Javar, H.A.; Larijani, B.; et al. Microfluidics for detection of exosomes and microRNAs in cancer: State of the art. Mol. Ther. Nucleic Acids 2022, 28, 758–791. [Google Scholar] [CrossRef]
  37. Sun, H.; Sun, R.; Song, X.; Gu, W.; Shao, Y. Mechanism and clinical value of exosomes and exosomal contents in regulating solid tumor radiosensitivity. J. Transl. Med. 2022, 20, 189. [Google Scholar] [CrossRef]
  38. Suire, C.N.; Hade, M.D. Extracellular Vesicles in Type 1 Diabetes: A Versatile Tool. Bioengineering 2022, 9, 105. [Google Scholar] [CrossRef]
  39. Nikdoust, F.; Pazoki, M.; Mohammadtaghizadeh, M.; Aghaali, M.K.; Amrovani, M. Exosomes: Potential Player in Endothelial Dysfunction in Cardiovascular Disease. Cardiovasc. Toxicol. 2022, 22, 225–235. [Google Scholar] [CrossRef]
  40. Feng, Z.Y.; Zhang, Q.Y.; Tan, J.; Xie, H.Q. Techniques for increasing the yield of stem cell-derived exosomes: What factors may be involved? Sci. China Life Sci. 2022, 65, 1325–1341. [Google Scholar] [CrossRef] [PubMed]
  41. Rajool Dezfuly, A.; Safaee, A.; Salehi, H. Therapeutic effects of mesenchymal stem cells-derived extracellular vesicles’ miRNAs on retinal regeneration: A review. Stem Cell Res. Ther. 2021, 12, 530. [Google Scholar] [CrossRef] [PubMed]
  42. Aoi, W.; Tanimura, Y. Roles of Skeletal Muscle-Derived Exosomes in Organ Metabolic and Immunological Communication. Front. Endocrinol 2021, 12, 697204. [Google Scholar] [CrossRef] [PubMed]
  43. Alharbi, M.G.; Lee, S.H.; Abdelazim, A.M.; Saadeldin, I.M.; Abomughaid, M.M. Role of Extracellular Vesicles in Compromising Cellular Resilience to Environmental Stressors. Biomed. Res. Int. 2021, 2021, 9912281. [Google Scholar] [CrossRef] [PubMed]
  44. Mirzaei, R.; Zamani, F.; Hajibaba, M.; Rasouli-Saravani, A.; Noroozbeygi, M.; Gorgani, M.; Hosseini-Fard, S.R.; Jalalifar, S.; Ajdarkosh, H.; Abedi, S.H.; et al. The pathogenic, therapeutic and diagnostic role of exosomal microRNA in the autoimmune diseases. J. Neuroimmunol. 2021, 358, 577640. [Google Scholar] [CrossRef]
  45. Bahrami, A.; Binabajm, M.M.; Ferns, A.G. Exosomes: Emerging modulators of signal transduction in colorectal cancer from molecular understanding to clinical application. Biomed. Pharmacother. 2021, 141, 111882. [Google Scholar] [CrossRef] [PubMed]
  46. Liew, F.F.; Chew, B.C.; Ooi, J. Wound Haling Properties of Exosomes—A Review and Modelling of Combinatorial Analysis Strategies. Curr. Mol. Med. 2022, 22, 165–191. [Google Scholar] [CrossRef] [PubMed]
  47. Yamada, M. Extracellular vesicles: Their emerging roles in the pathogenesis of respiratory diseases. Respir. Investig. 2021, 59, 302–311. [Google Scholar] [CrossRef] [PubMed]
  48. Huang, Y.; Kanada, M.; Ye, J.; Deng, Y.; He, Q.; Lei, Z.; Chen, Y.; Li, Y.; Qin, P.; Zhang, J.; et al. Exosome-mediated remodeling of the tumor microenvironment: From local to distant intercellular communication. Cancer Lett. 2022, 543, 215796. [Google Scholar] [CrossRef] [PubMed]
  49. Han, Z.; Chen, H.; Guo, Z.; Shen, J.; Luo, W.; Xie, F.; Wan, Y.; Wang, S.; Li, J.; He, J. Circular RNAs and Their Role in Exosomes. Front. Oncol. 2022, 12, 848341. [Google Scholar] [CrossRef]
  50. Thakur, A.; Johnson, A.; Jacobs, E.; Zhang, K.; Chen, J.; Wei, Z.; Lian, Q.; Chen, H.J. Energy Sources for Exosome Communication in a Cancer Microenvironment. Cancers 2022, 14, 1698. [Google Scholar] [CrossRef] [PubMed]
  51. Hsu, M.T.; Wang, Y.K.; Tseng, Y.J. Exosomal Proteins and Lipids as Potential Biomarkers for Lung Cancer Diagnosis, Prognosis, and Treatment. Cancers 2022, 14, 732. [Google Scholar] [CrossRef] [PubMed]
  52. Mahmoudi, A.; Butler, A.E.; Jamialahmadi, T.; Sahebkar, A. The role of exosomal miRNA in nonalcoholic fatty liver disease. J. Cell Physiol. 2022, 237, 2078–2094. [Google Scholar] [CrossRef] [PubMed]
  53. Yun, B.D.; Choi, Y.J.; Son, S.W.; Cipolla, G.A.; Berti, F.C.B.; Malheiros, D.; Oh, T.J.; Kuh, H.J.; Choi, S.Y.; Park, J.K. Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers. Int. J. Mol. Sci. 2022, 23, 930. [Google Scholar] [CrossRef] [PubMed]
  54. Zhang, H.; Xing, J.; Dai, Z.; Wang, D.; Tang, D. Exosomes: The key of sophisticated cell-cell communication and targeted metastasis in pancreatic cancer. Cell Commun. Signal 2022, 20, 9. [Google Scholar] [CrossRef] [PubMed]
  55. Rizk, N.I.; Abulsoud, A.I.; Kamal, M.M.; Kassem, D.H.; Hamdy, N.M. Exosomal-long non-coding RNAs journey in colorectal cancer: Evil and goodness faces of key players. Life Sci. 2022, 292, 120325. [Google Scholar] [CrossRef]
  56. Cione, E.; Cannataro, R.; Gallelli, L.; De Sarro, G.; Caroleo, M.C. Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options. Pharmaceuticals 2021, 14, 1257. [Google Scholar] [CrossRef] [PubMed]
  57. Tominaga, N. Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles. Cancers 2021, 13, 6303. [Google Scholar] [CrossRef]
  58. Teles, R.H.G.; Yano, R.S.; Villarinho, N.J.; Yamagata, A.S.; Jaeger, R.G.; Meybohm, P.; Burek, M.; Freitas, V.M. Advances in Breast Cancer Management and Extracellular Vesicle Research, a Bibliometric Analysis. Curr. Oncol. 2021, 28, 4504–4520. [Google Scholar] [CrossRef] [PubMed]
  59. Zou, J.; Peng, H.; Liu, Y. The Roles of Exosomes in Immunoregulation and Autoimmune Thyroid Diseases. Front. Immunol. 2021, 12, 757674. [Google Scholar] [CrossRef]
  60. Khodamoradi, K.; Golan, R.; Dullea, A.; Ramasamy, R. Exosomes as Potential Biomarkers for Erectile Dysfunction, Varicocele, and Testicular Injury. Sex Med. Rev. 2022, 10, 311–322. [Google Scholar] [CrossRef] [PubMed]
  61. Zhang, W.; Wang, Q.; Yang, Y.; Zhou, S.; Zhang, P.; Feng, T. The role of exosomal lncRNAs in cancer biology and clinical management. Exp. Mol. Med. 2021, 53, 1669–1673. [Google Scholar] [CrossRef] [PubMed]
  62. Chen, S.; He, R.; He, B.; Xu, L.; Zhang, S. Potential Roles of Exosomal lncRNAs in the Intestinal Mucosal Immune Barrier. J. Immunol. Res. 2021, 2021, 7183136. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, Q.; Xie, X. Association of Exosomal miR-210 with Signaling Pathways Implicated in Lung Cancer. Genes 2021, 12, 1248. [Google Scholar] [CrossRef] [PubMed]
  64. Heydari, R.; Abdollahpour-Alitappeh, M.; Shekari, F.; Meyfour, A. Emerging Role of Extracellular Vesicles in Biomarking the Gastrointestinal Diseases. Expert. Rev. Mol. Diagn. 2021, 21, 939–962. [Google Scholar] [CrossRef] [PubMed]
  65. Ghafouri-Fard, S.; Niazi, V.; Hussen, B.M.; Omrani, M.D.; Taheri, M.; Basiri, A. The Emerging Role of Exosomes in the Treatment of Human Disorders with a Special Focus on Mesenchymal Stem Cells-Derived Exosomes. Front. Cell Dev. Biol. 2021, 9, 653296. [Google Scholar] [CrossRef]
  66. Cricrì, G.; Bellucci, L.; Montini, G.; Collino, F. Urinary Extracellular Vesicles: Uncovering the Basis of the Pathological Processes in Kidney-Related Diseases. Int. J. Mol. Sci. 2021, 22, 6507. [Google Scholar] [CrossRef]
  67. Alhamwe, A.B.; Potaczek, D.P.; Miethe, S.; Alhamdan, F.; Hintz, L.; Magomedov, A.; Garn, H. Extracellular Vesicles and Asthma-More Than Just a Co-Existence. Int. J. Mol. Sci. 2021, 22, 4984. [Google Scholar] [CrossRef]
  68. Gysler, S.M.; Drapkin, R. Tumor innervation: Peripheral nerves take control of the tumor microenvironment. J. Clin. Investig. 2021, 131, e147276. [Google Scholar] [CrossRef]
  69. Qiu, Y.; Li, P.; Zhang, Z.; Wu, M. Insights into Exosomal Non-Coding RNAs Sorting Mechanism and Clinical Application. Front. Oncol. 2021, 11, 664904. [Google Scholar] [CrossRef]
  70. Albacete-Albacete, L.; Sánchez-Álvarez, M.; Del Pozo, M.A. Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C. Front. Immunol. 2021, 12, 671485. [Google Scholar] [CrossRef]
  71. Wu, H.; Fu, M.; Liu, J.; Chong, W.; Fang, Z.; Du, F.; Liu, Y.; Shang, L.; Li, L. The role and application of small extracellular vesicles in gastric cancer. Mol. Cancer 2021, 20, 71. [Google Scholar] [CrossRef] [PubMed]
  72. Sun, Y.F.; Pi, J.; Xu, J.F. Emerging Role of Exosomes in Tuberculosis: From Immunity Regulations to Vaccine and Immunotherapy. Front. Immunol. 2021, 12, 628973. [Google Scholar] [CrossRef] [PubMed]
  73. Perocheau, D.; Touramanidou, L.; Gurung, S.; Gissen, P.; Baruteau, J. Clinical applications for exosomes: Are we there yet? Br. J. Pharmacol. 2021, 178, 2375–2392. [Google Scholar] [CrossRef] [PubMed]
  74. Jafari, A.; Babajani, A.; Abdollahpour-Alitappeh, M.; Ahmadi, N.; Rezaei-Tavirani, M. Exosomes and cancer: From molecular mechanisms to clinical applications. Med. Oncol. 2021, 38, 45. [Google Scholar] [CrossRef]
  75. Casari, I.; Howard, J.A.; Robless, E.E.; Falasca, M. Exosomal integrins and their influence on pancreatic cancer progression and metastasis. Cancer Lett. 2021, 507, 124–134. [Google Scholar] [CrossRef]
  76. Lizarraga-Valderrama, L.R.; Sheridan, G.K. Extracellular vesicles and intercellular communication in the central nervous system. FEBS Lett. 2021, 595, 1391–1410. [Google Scholar] [CrossRef]
  77. Esfandyari, S.; Elkafas, H.; Chugh, R.M.; Park, H.S.; Navarro, A.; Al-Hendy, A. Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy. Int. J. Mol. Sci. 2021, 22, 2165. [Google Scholar] [CrossRef]
  78. Saludas, L.; Oliveira, C.C.; Roncal, C.; Ruiz-Villalba, A.; Prósper, F.; Garbayo, E.; Blanco-Prieto, M.J. Extracellular Vesicle-Based Therapeutics for Heart Repair. Nanomaterials 2021, 11, 570. [Google Scholar] [CrossRef]
  79. Wei, X.; Shi, Y.; Dai, Z.; Wang, P.; Meng, X.; Yin, B. Underlying metastasis mechanism and clinical application of exosomal circular RNA in tumors (Review). Int. J. Oncol. 2021, 58, 289–297. [Google Scholar] [CrossRef]
  80. Makarova, J.; Turchinovich, A.; Shkurnikov, M.; Tonevitsky, A. Extracellular miRNAs and Cell-Cell Communication: Problems and Prospects. Trends Biochem. Sci. 2021, 46, 640–651. [Google Scholar] [CrossRef]
  81. Amintas, S.; Vendrely, V.; Dupin, C.; Buscail, L.; Laurent, C.; Bournet, B.; Merlio, J.P.; Bedel, A.; Moreau-Gaudry, F.; Boutin, J.; et al. Next-Generation Cancer Biomarkers: Extracellular Vesicle DNA as a Circulating Surrogate of Tumor DNA. Front. Cell Dev. Biol. 2021, 8, 622048. [Google Scholar] [CrossRef]
  82. Røsand, Ø.; Høydal, M.A. Cardiac Exosomes in Ischemic Heart Disease—A Narrative Review. Diagnostics 2021, 11, 269. [Google Scholar] [CrossRef] [PubMed]
  83. Fareez, I.M.; Seng, W.Y.; Zaki, R.M.; Shafiq, A.; Izwan, I.M. Molecular and Epigenetic Basis of Extracellular Vesicles Cell Repair Phenotypes in Targeted Organ-specific Regeneration. Curr. Mol. Med. 2022, 22, 132–150. [Google Scholar] [CrossRef]
  84. Marostica, G.; Gelibter, S.; Gironi, M.; Nigro, A.; Furlan, R. Extracellular Vesicles in Neuroinflammation. Front. Cell Dev. Biol. 2021, 8, 623039. [Google Scholar] [CrossRef] [PubMed]
  85. Tan, K.L.; Chia, W.C.; How, C.W.; Tor, Y.S.; Show, P.L.; Looi, Q.H.D.; Foo, J.B. Benchtop Isolation and Characterisation of Small Extracellular Vesicles from Human Mesenchymal Stem Cells. Mol. Biotechnol. 2021, 63, 780–791. [Google Scholar] [CrossRef]
  86. Poon, I.K.H.; Parkes, M.A.F.; Jiang, L.; Atkin-Smith, G.K.; Tixeira, R.; Gregory, C.D.; Ozkocak, D.C.; Rutter, S.F.; Caruso, S.; Santavanond, J.P.; et al. Moving beyond size and phosphatidylserine exposure: Evidence for a diversity of apoptotic cell-derived extracellular vesicles in vitro. J. Extracell. Vesicles 2019, 8, 1608786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Matsumura, S.; Minamisawa, T.; Suga, K.; Kishita, H.; Akagi, T.; Ichiki, T.; Ichikawa, Y.; Shiba, K. Subtypes of tumour cell-derived small extracellular vesicles having differently externalized phosphatidylserine. J. Extracell. Vesicles 2019, 8, 1579541. [Google Scholar] [CrossRef] [Green Version]
  88. Oyarce, K.; Cepeda, M.Y.; Lagos, R.; Garrido, C.; Vega-Letter, A.M.; Garcia-Robles, M.; Luz-Crawford, P.; Elizondo-Vega, R. Neuroprotective and Neurotoxic Effects of Glial-Derived Exosomes. Front. Cell Neurosci. 2022, 16, 920686. [Google Scholar] [CrossRef]
  89. Hu, C.; Jiang, W.; Lv, M.; Fan, S.; Lu, Y.; Wu, Q.; Pi, J. Potentiality of Exosomal Proteins as Novel Cancer Biomarkers for Liquid Biopsy. Front. Immunol. 2022, 13, 792046. [Google Scholar] [CrossRef]
  90. Bano, R.; Ahmad, F.; Mohsin, M. A perspective on the isolation and characterization of extracellular vesicles from different biofluids. RSC Adv. 2021, 11, 19598–19615. [Google Scholar] [CrossRef]
  91. Gurunathan, S.; Kang, M.H.; Song, H.; Kim, N.H.; Kim, J.H. The role of extracellular vesicles in animal reproduction and diseases. J. Anim. Sci. Biotechnol. 2022, 13, 62. [Google Scholar] [CrossRef] [PubMed]
  92. Kawaguchi, N.; Nakanishi, T. Stem Cell Studies in Cardiovascular Biology and Medicine: A Possible Key Role of Macrophages. Biology 2022, 11, 122. [Google Scholar] [CrossRef] [PubMed]
  93. Pulliam, L.; Sun, B.; Mustapic, M.; Chawla, S.; Kapogiannis, D. Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer’s disease. J. Neurovirol. 2019, 25, 702–709. [Google Scholar] [CrossRef]
  94. Salomon, C.; Nuzhat, Z.; Dixon, C.L.; Menon, R. Placental Exosomes During Gestation: Liquid Biopsies Carrying Signals for the Regulation of Human Parturition. Curr. Pharm. Des. 2018, 24, 974–982. [Google Scholar] [CrossRef]
  95. Carnino, J.M.; Lee, H. Extracellular vesicles in respiratory disease. Adv. Clin. Chem. 2022, 108, 105–127. [Google Scholar] [CrossRef] [PubMed]
  96. Pathania, A.S.; Prathipati, P.; Challagundla, K.B. New insights into exosome mediated tumor-immune escape: Clinical perspectives and therapeutic strategies. Biochim. Biophys. Acta Rev. Cancer 2021, 1876, 188624. [Google Scholar] [CrossRef]
  97. Wu, J.; Xie, Q.; Liu, Y.; Gao, Y.; Qu, Z.; Mo, L.; Xu, Y.; Chen, R.; Shi, L. A Small Vimentin-Binding Molecule Blocks Cancer Exosome Release and Reduces Cancer Cell Mobility. Front. Pharmacol. 2021, 12, 627394. [Google Scholar] [CrossRef]
  98. Grieco, G.E.; Fignani, D.; Formichi, C.; Nigi, L.; Licata, G.; Maccora, C.; Brusco, N.; Sebastiani, G.; Dotta, F. Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools. Front. Immunol. 2021, 12, 682948. [Google Scholar] [CrossRef]
  99. Burillo, J.; Fernández-Rhodes, M.; Piquero, M.; López-Alvarado, P.; Menéndez, J.C.; Jiménez, B.; González-Blanco, C.; Marqués, P.; Guillén, C.; Benito, M. Human amylin aggregates release within exosomes as a protective mechanism in pancreatic β cells: Pancreatic β-hippocampal cell communication. Biochim. Biophys. Acta Mol. Cell Res. 2021, 1868, 118971. [Google Scholar] [CrossRef]
  100. Wang, C.A.; Tsai, S.J. Regulation of lymphangiogenesis by extracellular vesicles in cancer metastasis. Exp. Biol. Med. 2021, 246, 2048–2056. [Google Scholar] [CrossRef]
  101. Kim, K.S.; Park, J.I.; Oh, N.; Cho, H.J.; Park, J.H.; Park, K.S. ELK3 expressed in lymphatic endothelial cells promotes breast cancer progression and metastasis through exosomal miRNAs. Sci. Rep. 2019, 9, 8418. [Google Scholar] [CrossRef] [Green Version]
  102. Wang, D.; Zhang, W.; Zhang, C.; Wang, L.; Chen, H.; Xu, J. Exosomal non-coding RNAs have a significant effect on tumor metastasis. Mol. Ther. Nucleic Acids 2022, 29, 16–35. [Google Scholar] [CrossRef] [PubMed]
  103. Monti, M.; Lunardini, S.; Magli, I.A.; Campi, R.; Primiceri, G.; Berardinelli, F.; Amparore, D.; Terracciano, D.; Lucarelli, G.; Schips, L.; et al. Micro-RNAs Predict Response to Systemic Treatments in Metastatic Renal Cell Carcinoma Patients: Results from a Systematic Review of the Literature. Biomedicines 2022, 10, 1287. [Google Scholar] [CrossRef] [PubMed]
  104. Yang, M.; Sun, M.; Zhang, H. The Interaction Between Epigenetic Changes, EMT, and Exosomes in Predicting Metastasis of Colorectal Cancers (CRC). Front. Oncol. 2022, 12, 879848. [Google Scholar] [CrossRef]
  105. Khera, A.; Alajangi, H.K.; Khajuria, A.; Barnwal, R.P.; Kumar, S.; Singh, G. Highlighting the potential role of Exosomes as the targeted nano-therapeutic carrier in metastatic breast cancer. Curr. Drug Deliv. 2022; in press. [Google Scholar] [CrossRef]
  106. Tămaș, F.; Bălașa, R.; Manu, D.; Gyorki, G.; Chinezu, R.; Tămaș, C.; Bălașa, A. The Importance of Small Extracellular Vesicles in the Cerebral Metastatic Process. Int. J. Mol. Sci. 2022, 23, 1449. [Google Scholar] [CrossRef] [PubMed]
  107. Sunami, Y.; Häußler, J.; Zourelidis, A.; Kleeff, J. Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes. Cancers 2022, 14, 744. [Google Scholar] [CrossRef]
  108. Bai, S.; Wei, Y.; Liu, R.; Xu, R.; Xiang, L.; Du, J. Role of tumour-derived exosomes in metastasis. Biomed. Pharmacother. 2022, 147, 112657. [Google Scholar] [CrossRef]
  109. Zhou, H.; He, X.; He, Y.; Ou, C.; Cao, P. Exosomal circRNAs: Emerging Players in Tumor Metastasis. Front. Cell Dev. Biol. 2021, 9, 786224. [Google Scholar] [CrossRef]
  110. Pascual-Antón, L.; Cardeñes, B.; Sainz de la Cuesta, R.; González-Cortijo, L.; López-Cabrera, M.; Cabañas, C.; Sandoval, P. Mesothelial-to-Mesenchymal Transition and Exosomes in Peritoneal Metastasis of Ovarian Cancer. Int. J. Mol. Sci. 2021, 22, 11496. [Google Scholar] [CrossRef]
  111. Shen, B.; Sun, K. Exosomal circular RNAs: A new frontier in the metastasis of digestive system tumors. Oncol. Lett. 2021, 22, 826. [Google Scholar] [CrossRef]
  112. Singh, M.; Agarwal, S.; Agarwal, V.; Mall, S.; Pancham, P.; Mani, S. Current theranostic approaches for metastatic cancers through hypoxia-induced exosomal packaged cargo. Life Sci. 2021, 286, 120017. [Google Scholar] [CrossRef] [PubMed]
  113. Yang, X.; Zhang, Y.; Zhang, Y.; Zhang, S.; Qiu, L.; Zhuang, Z.; Wei, M.; Deng, X.; Wang, Z.; Han, J. The Key Role of Exosomes on the Pre-metastatic Niche Formation in Tumors. Front. Mol. Biosci. 2021, 8, 703640. [Google Scholar] [CrossRef] [PubMed]
  114. Mkhobongo, B.; Chandran, R.; Abrahamse, H. The Role of Melanoma Cell-Derived Exosomes (MTEX) and Photodynamic Therapy (PDT) within a Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 9726. [Google Scholar] [CrossRef] [PubMed]
  115. Chen, H.; Chengalvala, V.; Hu, H.; Sun, D. Tumor-derived exosomes: Nanovesicles made by cancer cells to promote cancer metastasis. Acta Pharm. Sin. B 2021, 11, 2136–2149. [Google Scholar] [CrossRef] [PubMed]
  116. Jiang, C.; Zhang, N.; Hu, X.; Wang, H. Tumor-associated exosomes promote lung cancer metastasis through multiple mechanisms. Mol. Cancer 2021, 20, 117. [Google Scholar] [CrossRef]
  117. Seibold, T.; Waldenmaier, M.; Seufferlein, T.; Eiseler, T. Small Extracellular Vesicles and Metastasis-Blame the Messenger. Cancers 2021, 13, 4380. [Google Scholar] [CrossRef]
  118. Zhao, L.; Ma, X.; Yu, J. Exosomes and organ-specific metastasis. Mol. Ther. Methods Clin. Dev. 2021, 22, 133–147. [Google Scholar] [CrossRef]
  119. Storti, G.; Scioli, M.G.; Kim, B.S.; Terriaca, S.; Fiorelli, E.; Orlandi, A.; Cervelli, V. Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity? Cells 2021, 10, 2117. [Google Scholar] [CrossRef]
  120. Zarin, B.; Rafiee, L.; Daneshpajouhnejad, P.; Haghjooy Javanmard, S. A review on the role of CAFs and CAF-derived exosomes in progression and metastasis of digestive system cancers. Tumour Biol. 2021, 43, 141–157. [Google Scholar] [CrossRef]
  121. Yin, L.; Liu, X.; Shao, X.; Feng, T.; Xu, J.; Wang, Q.; Hua, S. The role of exosomes in lung cancer metastasis and clinical applications: An updated review. J. Transl. Med. 2021, 19, 312. [Google Scholar] [CrossRef]
  122. Chen, X.; Wang, H.; Huang, Y.; Chen, Y.; Chen, C.; Zhuo, W.; Teng, L. Comprehensive Roles and Future Perspectives of Exosomes in Peritoneal Metastasis of Gastric Cancer. Front. Oncol. 2021, 11, 684871. [Google Scholar] [CrossRef] [PubMed]
  123. Balaji, S.; Kim, U.; Muthukkaruppan, V.; Vanniarajan, A. Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition. Life Sci. 2021, 280, 119750. [Google Scholar] [CrossRef] [PubMed]
  124. Gao, J.; Li, S.; Xu, Q.; Zhang, X.; Huang, M.; Dai, X.; Liu, L. Exosomes Promote Pre-Metastatic Niche Formation in Gastric Cancer. Front. Oncol. 2021, 11, 652378. [Google Scholar] [CrossRef] [PubMed]
  125. Al-Humaidi, R.B.; Fayed, B.; Sharif, S.I.; Noreddin, A.; Soliman, S.S.M. Role of Exosomes in Breast Cancer Management: Evidence-Based Review. Curr. Cancer Drug Targets 2021, 21, 666–675. [Google Scholar] [CrossRef] [PubMed]
  126. Tan, Y.; Luo, X.; Lv, W.; Hu, W.; Zhao, C.; Xiong, M.; Yi, Y.; Wang, D.; Wang, Y.; Wang, H.; et al. Tumor-derived exosomal components: The multifaceted roles and mechanisms in breast cancer metastasis. Cell Death Dis. 2021, 12, 547. [Google Scholar] [CrossRef] [PubMed]
  127. Gao, Z.; Pang, B.; Li, J.; Gao, N.; Fan, T.; Li, Y. Emerging Role of Exosomes in Liquid Biopsy for Monitoring Prostate Cancer Invasion and Metastasis. Front. Cell Dev. Biol. 2021, 9, 679527. [Google Scholar] [CrossRef]
  128. Wang, X.; Zhou, Y.; Ding, K. Roles of exosomes in cancer chemotherapy resistance, progression, metastasis and immunity, and their clinical applications (Review). Int. J. Oncol. 2021, 59, 44. [Google Scholar] [CrossRef]
  129. Danac, J.M.C.; Uy, A.G.G.; Garcia, R.L. Exosomal microRNAs in colorectal cancer: Overcoming barriers of the metastatic cascade (Review). Int. J. Mol. Med. 2021, 47, 112. [Google Scholar] [CrossRef]
  130. Akoto, T.; Saini, S. Role of Exosomes in Prostate Cancer Metastasis. Int. J. Mol. Sci. 2021, 22, 3528. [Google Scholar] [CrossRef]
  131. Fu, C.; Zhang, Q.; Wang, A.; Yang, S.; Jiang, Y.; Bai, L.; Wei, Q. EWI-2 controls nucleocytoplasmic shuttling of EGFR signaling molecules and miRNA sorting in exosomes to inhibit prostate cancer cell metastasis. Mol. Oncol. 2021, 15, 1543–1565. [Google Scholar] [CrossRef]
  132. Peng, L.; Wang, D.; Han, Y.; Huang, T.; He, X.; Wang, J.; Ou, C. Emerging Role of Cancer-Associated Fibroblasts-Derived Exosomes in Tumorigenesis. Front. Immunol. 2022, 12, 795372. [Google Scholar] [CrossRef]
  133. Tang, L.B.; Ma, S.X.; Chen, Z.H.; Huang, Q.Y.; Wu, L.Y.; Wang, Y.; Zhao, R.C.; Xiong, L.X. Exosomal microRNAs: Pleiotropic Impacts on Breast Cancer Metastasis and Their Clinical Perspectives. Biology 2021, 10, 307. [Google Scholar] [CrossRef] [PubMed]
  134. Guo, Y.; Ji, X.; Liu, J.; Fan, D.; Zhou, Q.; Chen, C.; Wang, W.; Wang, G.; Wang, H.; Yuan, W.; et al. Effects of exosomes on pre-metastatic niche formation in tumors. Mol. Cancer 2019, 18, 39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Jia, Z.; Jia, J.; Yao, L.; Li, Z. Crosstalk of Exosomal Non-Coding RNAs in The Tumor Microenvironment: Novel Frontiers. Front. Immunol. 2022, 13, 900155. [Google Scholar] [CrossRef]
  136. Su, M.T.; Kumata, S.; Endo, S.; Okada, Y.; Takai, T. LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs. Oncoimmunology 2022, 11, 2060907. [Google Scholar] [CrossRef] [PubMed]
  137. Sendi, H.; Yazdimamaghani, M.; Hu, M.; Sultanpuram, N.; Wang, J.; Moody, A.S.; McCabe, E.; Zhang, J.; Graboski, A.; Li, L.; et al. Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis. Cancer Res. 2022, 82, 105–113. [Google Scholar] [CrossRef] [PubMed]
  138. Yang, S.J.; Wang, D.D.; Zhong, S.L.; Chen, W.Q.; Wang, F.L.; Zhang, J.; Xu, W.X.; Xu, D.; Zhang, Q.; Li, J.; et al. Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis. Cell Death Dis. 2021, 12, 420. [Google Scholar] [CrossRef]
  139. Chen, S.; Chen, X.; Qiu, J.; Chen, P.; Han, X.; Wu, Y.; Zhuang, J.; Yang, M.; Wu, C.; Wu, N.; et al. Exosomes derived from retinoblastoma cells enhance tumour deterioration by infiltrating the microenvironment. Oncol. Rep. 2021, 45, 278–290. [Google Scholar] [CrossRef]
  140. Moradi-Chaleshtori, M.; Bandehpour, M.; Heidari, N.; Mohammadi-Yeganeh, S.; Mahmoud Hashemi, S. Exosome-mediated miR-33 transfer induces M1 polarization in mouse macrophages and exerts antitumor effect in 4T1 breast cancer cell line. Int. Immunopharmacol. 2021, 90, 107198. [Google Scholar] [CrossRef]
  141. Zhao, M.; Zhuang, A.; Fang, Y. Cancer-Associated Fibroblast-Derived Exosomal miRNA-320a Promotes Macrophage M2 Polarization In Vitro by Regulating PTEN/PI3Kγ Signaling in Pancreatic Cancer. J. Oncol. 2022, 2022, 9514697. [Google Scholar] [CrossRef]
  142. Qi, M.; Xia, Y.; Wu, Y.; Zhang, Z.; Wang, X.; Lu, L.; Dai, C.; Song, Y.; Xu, K.; Ji, W.; et al. Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression. Nat. Commun. 2022, 13, 897. [Google Scholar] [CrossRef] [PubMed]
  143. Yoshida, K.; Yokoi, A.; Kato, T.; Ochiya, T.; Yamamoto, Y. The clinical impact of intra- and extracellular miRNAs in ovarian cancer. Cancer Sci. 2020, 111, 3435–3444. [Google Scholar] [CrossRef] [PubMed]
  144. Yang, C.; Kim, H.S.; Song, G.; Lim, W. The potential role of exosomes derived from ovarian cancer cells for diagnostic and therapeutic approaches. J. Cell Physiol. 2019, 234, 21493–21503. [Google Scholar] [CrossRef] [PubMed]
  145. Wu, X.G.; Zhou, C.F.; Zhang, Y.M.; Yan, R.M.; Wei, W.F.; Chen, X.J.; Yi, H.Y.; Liang, L.J.; Fan, L.S.; Liang, L.; et al. Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma. Angiogenesis 2019, 22, 397–410. [Google Scholar] [CrossRef]
  146. Chen, K.; Wang, Q.; Liu, X.; Wang, F.; Yang, Y.; Tian, X. Hypoxic pancreatic cancer derived exosomal miR-30b-5p promotes tumor angiogenesis by inhibiting GJA1 expression. Int. J. Biol. Sci. 2022, 18, 1220–1237. [Google Scholar] [CrossRef]
  147. Duréndez-Sáez, E.; Torres-Martinez, S.; Calabuig-Fariñas, S.; Meri-Abad, M.; Ferrero-Gimeno, M.; Camps, C. Exosomal microRNAs in non-small cell lung cancer. Transl. Cancer Res. 2021, 10, 3128–3139. [Google Scholar] [CrossRef]
  148. Li, C.; Zhou, T.; Chen, J.; Li, R.; Chen, H.; Luo, S.; Chen, D.; Cai, C.; Li, W. The role of Exosomal miRNAs in cancer. J. Transl. Med. 2022, 20, 6. [Google Scholar] [CrossRef]
  149. Xu, J.L.; Xu, W.X.; Tang, J.H. Exosomal circRNAs: A new communication method in cancer. Am. J. Transl. Res. 2021, 13, 12913–12928. [Google Scholar]
  150. Tominaga, N.; Kosaka, N.; Ono, M.; Katsuda, T.; Yoshioka, Y.; Tamura, K.; Lötvall, J.; Nakagama, H.; Ochiya, T. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat. Commun. 2015, 6, 6716. [Google Scholar] [CrossRef] [Green Version]
  151. Geng, S.; Tu, S.; Bai, Z.; Geng, Y. Exosomal lncRNA LINC01356 Derived from Brain Metastatic Nonsmall-Cell Lung Cancer Cells Remodels the Blood-Brain Barrier. Front. Oncol. 2022, 12, 825899. [Google Scholar] [CrossRef]
  152. Curtaz, C.J.; Reifschläger, L.; Strähle, L.; Feldheim, J.; Feldheim, J.J.; Schmitt, C.; Kiesel, M.; Herbert, S.L.; Wöckel, A.; Meybohm, P.; et al. Analysis of microRNAs in Exosomes of Breast Cancer Patients in Search of Molecular Prognostic Factors in Brain Metastases. Int. J. Mol. Sci. 2022, 23, 3683. [Google Scholar] [CrossRef] [PubMed]
  153. Busatto, S.; Morad, G.; Guo, P.; Moses, M.A. The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier. FASEB Bioadv. 2021, 3, 665–675. [Google Scholar] [CrossRef] [PubMed]
  154. Wu, D.; Deng, S.; Li, L.; Liu, T.; Zhang, T.; Li, J.; Yu, Y.; Xu, Y. TGF-β1-mediated exosomal lnc-MMP2-2 increases blood-brain barrier permeability via the miRNA-1207-5p/EPB41L5 axis to promote non-small cell lung cancer brain metastasis. Cell Death Dis. 2021, 12, 721. [Google Scholar] [CrossRef]
  155. Yokoi, A.; Yoshioka, Y.; Yamamoto, Y.; Ishikawa, M.; Ikeda, S.I.; Kato, T.; Kiyono, T.; Takeshita, F.; Kajiyama, H.; Kikkawa, F.; et al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat. Commun. 2017, 8, 14470. [Google Scholar] [CrossRef] [Green Version]
  156. Wang, G.; Xie, L.; Li, B.; Sang, W.; Yan, J.; Li, J.; Tian, H.; Li, W.; Zhang, Z.; Tian, Y.; et al. A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis. Nat. Commun. 2021, 12, 5733. [Google Scholar] [CrossRef] [PubMed]
  157. Xu, Z.; Tsai, H.I.; Xiao, Y.; Wu, Y.; Su, D.; Yang, M.; Zha, H.; Yan, F.; Liu, X.; Cheng, F.; et al. Engineering Programmed Death Ligand-1/Cytotoxic T-Lymphocyte-Associated Antigen-4 Dual-Targeting Nanovesicles for Immunosuppressive Therapy in Transplantation. ACS Nano 2020, 14, 7959–7969. [Google Scholar] [CrossRef]
  158. Xie, L.; Li, J.; Wang, G.; Sang, W.; Xu, M.; Li, W.; Yan, J.; Li, B.; Zhang, Z.; Zhao, Q.; et al. Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy. J. Am. Chem. Soc. 2022, 144, 787–797. [Google Scholar] [CrossRef]
  159. Chen, J.; Song, Y.; Miao, F.; Chen, G.; Zhu, Y.; Wu, N.; Pang, L.; Chen, Z.; Chen, X. PDL1-positive exosomes suppress antitumor immunity by inducing tumor-specific CD8+ T cell exhaustion during metastasis. Cancer Sci. 2021, 112, 3437–3454. [Google Scholar] [CrossRef]
  160. Liu, N.; Zhang, J.; Yin, M.; Liu, H.; Zhang, X.; Li, J.; Yan, B.; Guo, Y.; Zhou, J.; Tao, J.; et al. Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization. Mol. Ther. 2021, 29, 2321–2334. [Google Scholar] [CrossRef]
  161. Shu, S.; Matsuzaki, J.; Want, M.Y.; Conway, A.; Benjamin-Davalos, S.; Allen, C.L.; Koroleva, M.; Battaglia, S.; Odunsi, A.; Minderman, H.; et al. An Immunosuppressive Effect of Melanoma-derived Exosomes on NY-ESO-1 Antigen-specific Human CD8+ T Cells is Dependent on IL-10 and Independent of BRAFV600E Mutation in Melanoma Cell Lines. Immunol. Investig. 2020, 49, 744–757. [Google Scholar] [CrossRef]
  162. Chen, G.; Huang, A.C.; Zhang, W.; Zhang, G.; Wu, M.; Xu, W.; Yu, Z.; Yang, J.; Wang, B.; Sun, H.; et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 2018, 560, 382–386. [Google Scholar] [CrossRef] [PubMed]
  163. Rupareliya, C.; Naqvi, S.; Jani, V.B. Acute Inflammatory Demyelinating Polyneuroradiculopathy with Ipilimumab in Metastatic Melanoma: A Case Report and Review of Literature. Cureus 2017, 9, e1310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Mastoraki, A.; Gkiala, A.; Theodoroleas, G.; Mouchtouri, E.; Strimpakos, A.; Papagiannopoulou, D.; Schizas, D. Metastatic malignant melanoma of the breast: Report of a case and review of the literature. Folia. Med. 2022, 64, 354–358. [Google Scholar] [CrossRef] [PubMed]
  165. Gracia-Hernandez, M.; Munoz, Z.; Villagra, A. Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers. Cancers 2021, 13, 6180. [Google Scholar] [CrossRef] [PubMed]
  166. Ma, B.; Anandasabapathy, N. Immune Checkpoint Blockade and Skin Toxicity Pathogenesis. J. Investig. Dermatol. 2022, 142, 951–959. [Google Scholar] [CrossRef] [PubMed]
  167. Dietz, H.; Weinmann, S.C.; Salama, A.K. Checkpoint Inhibitors in Melanoma Patients with Underlying Autoimmune Disease. Cancer Manag. Res. 2021, 13, 8199–8208. [Google Scholar] [CrossRef] [PubMed]
  168. Sun, Y.M.; Li, W.; Chen, Z.Y.; Wang, Y. Risk of Pneumonitis Associated with Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis. Front. Oncol. 2021, 11, 651553. [Google Scholar] [CrossRef]
  169. Zawit, M.; Swami, U.; Awada, H.; Arnouk, J.; Milhem, M.; Zakharia, Y. Current status of intralesional agents in treatment of malignant melanoma. Ann. Transl. Med. 2021, 9, 1038. [Google Scholar] [CrossRef]
  170. Sakellariou, S.; Zouki, D.N.; Ziogas, D.C.; Pouloudi, D.; Gogas, H.; Delladetsima, I. Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: A case report and literature review. BMC Gastroenterol. 2021, 21, 227. [Google Scholar] [CrossRef]
  171. Li, J.H.; Huang, L.J.; Zhou, H.L.; Shan, Y.M.; Chen, F.M.; Lehto, V.P.; Xu, W.J.; Luo, L.Q.; Yu, H.J. Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy. Acta Pharmacol. Sin. 2022, 43, 2749–2758. [Google Scholar] [CrossRef]
  172. Archilla-Ortega, A.; Domuro, C.; Martin-Liberal, J.; Muñoz, P. Blockade of novel immune checkpoints and new therapeutic combinations to boost antitumor immunity. J. Exp. Clin. Cancer Res. 2022, 41, 62. [Google Scholar] [CrossRef] [PubMed]
  173. Ye, L.; Zhu, Z.; Chen, X.; Zhang, H.; Huang, J.; Gu, S.; Zhao, X. The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target. Cells 2021, 10, 3247. [Google Scholar] [CrossRef] [PubMed]
  174. Palicelli, A.; Croci, S.; Bisagni, A.; Zanetti, E.; De Biase, D.; Melli, B.; Sanguedolce, F.; Ragazzi, M.; Zanelli, M.; Chaux, A.; et al. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 12330. [Google Scholar] [CrossRef] [PubMed]
  175. Awadasseid, A.; Wu, Y.; Zhang, W. Advance investigation on synthetic small-molecule inhibitors targeting PD-1/PD-L1 signaling pathway. Life Sci. 2021, 282, 119813. [Google Scholar] [CrossRef]
  176. Xing, K.; Zhou, P.; Li, J.; Liu, M.; Zhang, W.E. Inhibitory Effect of PD-1/PD-L1 and Blockade Immunotherapy in Leukemia. Comb. Chem. High Throughput Screen 2021, 25, 1399–1410. [Google Scholar] [CrossRef]
  177. Huang, H.W.; Chang, C.C.; Wang, C.S.; Lin, K.H. Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development. Cells 2021, 10, 67. [Google Scholar] [CrossRef]
  178. Han, J.; Xu, X.; Liu, Z.; Li, Z.; Wu, Y.; Zuo, D. Recent advances of molecular mechanisms of regulating PD-L1 expression in melanoma. Int. Immunopharmacol. 2020, 88, 106971. [Google Scholar] [CrossRef]
  179. Guan, L.; Wu, B.; Li, T.; Beer, L.A.; Sharma, G.; Li, M.; Lee, C.N.; Liu, S.; Yang, C.; Huang, L.; et al. HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors. Nat. Commun. 2022, 13, 4078. [Google Scholar] [CrossRef]
  180. Zhang, J.; Zhu, Y.; Guan, M.; Liu, Y.; Lv, M.; Zhang, C.; Zhang, H.; Zhang, Z. Isolation of circulating exosomes and identification of exosomal PD-L1 for predicting immunotherapy response. Nanoscale 2022, 14, 8995–9003. [Google Scholar] [CrossRef]
  181. Shen, D.D.; Pang, J.R.; Bi, Y.P.; Zhao, L.F.; Li, Y.R.; Zhao, L.J.; Gao, Y.; Wang, B.; Wang, N.; Wei, L.; et al. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer. Mol. Cancer 2022, 21, 75. [Google Scholar] [CrossRef]
  182. Turiello, R.; Capone, M.; Morretta, E.; Monti, M.C.; Madonna, G.; Azzaro, R.; Del Gaudio, P.; Simeone, E.; Sorrentino, A.; Ascierto, P.A.; et al. Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents. J. Immunother. Cancer 2022, 10, e004043. [Google Scholar] [CrossRef] [PubMed]
  183. Zhang, W.; Zhong, W.; Wang, B.; Yang, J.; Yang, J.; Yu, Z.; Qin, Z.; Shi, A.; Xu, W.; Zheng, C.; et al. ICAM-1-mediated adhesion is a prerequisite for exosome-induced T cell suppression. Dev. Cell 2022, 57, 329–343.e7. [Google Scholar] [CrossRef] [PubMed]
  184. Zanella, A.; Vautrot, V.; Aubin, F.; Avoscan, L.; Samimi, M.; Garrido, C.; Gobbo, J.; Nardin, C. PD-L1 in circulating exosomes of Merkel cell carcinoma. Exp. Dermatol. 2022, 31, 869–877. [Google Scholar] [CrossRef] [PubMed]
  185. Hu, L.; Chen, W.; Zhou, S.; Zhu, G. ExoHCR: A sensitive assay to profile PD-L1 level on tumor exosomes for immunotherapeutic prognosis. Biophys. Rep. 2020, 6, 290–298. [Google Scholar] [CrossRef]
  186. Chen, X.; Du, Z.; Huang, M.; Wang, D.; Fong, W.P.; Liang, J.; Fan, L.; Wang, Y.; Yang, H.; Chen, Z.; et al. Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection. Cancer Immunol. Immunother. 2022, 71, 661–674. [Google Scholar] [CrossRef] [PubMed]
  187. Qiu, Y.; Yang, Y.; Yang, R.; Liu, C.; Hsu, J.M.; Jiang, Z.; Sun, L.; Wei, Y.; Li, C.W.; Yu, D.; et al. Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer. Oncogene 2021, 40, 4992–5001. [Google Scholar] [CrossRef]
  188. Wang, R.; Xu, A.; Zhang, X.; Wu, J.; Freywald, A.; Xu, J.; Xiang, J. Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway. Cell Mol. Immunol. 2017, 14, 529–545. [Google Scholar] [CrossRef] [Green Version]
  189. Morrissey, S.M.; Yan, J. Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy. Trends Cancer 2020, 6, 550–558. [Google Scholar] [CrossRef]
  190. Zhou, K.; Guo, S.; Li, F.; Sun, Q.; Liang, G. Exosomal PD-L1: New Insights into Tumor Immune Escape Mechanisms and Therapeutic Strategies. Front. Cell Dev. Biol. 2020, 8, 569219. [Google Scholar] [CrossRef]
  191. Xie, F.; Xu, M.; Lu, J.; Mao, L.; Wang, S. The role of exosomal PD-L1 in tumor progression and immunotherapy. Mol. Cancer 2019, 18, 146. [Google Scholar] [CrossRef]
  192. Liu, J.; Peng, X.; Yang, S.; Li, X.; Huang, M.; Wei, S.; Zhang, S.; He, G.; Zheng, H.; Fan, Q.; et al. Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: Biological function and potential therapy strategies. Cell Commun. Signal. 2022, 20, 14. [Google Scholar] [CrossRef] [PubMed]
  193. Yoh, K.E.; Lowe, C.J.; Mahajan, S.; Suttmann, R.; Nguy, T.; Reichelt, M.; Yang, J.; Melendez, R.; Li, Y.; Molinero, L.; et al. Enrichment of circulating tumor-derived extracellular vesicles from human plasma. J. Immunol. Methods 2021, 490, 112936. [Google Scholar] [CrossRef] [PubMed]
  194. Wu, F.; Gu, Y.; Kang, B.; Heskia, F.; Pachot, A.; Bonneville, M.; Wei, P.; Liang, J. PD-L1 detection on circulating tumor-derived extracellular vesicles (T-EVs) from patients with lung cancer. Transl. Lung Cancer Res. 2021, 10, 2441–2451. [Google Scholar] [CrossRef] [PubMed]
  195. Kim, D.H.; Kim, H.; Choi, Y.J.; Kim, S.Y.; Lee, J.E.; Sung, K.J.; Sung, Y.H.; Pack, C.G.; Jung, M.K.; Han, B.; et al. Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer. Exp. Mol. Med. 2019, 51, 1–13. [Google Scholar] [CrossRef] [Green Version]
  196. Wang, Y.; Niu, X.; Cheng, Y.; Zhang, Y.; Xia, L.; Xia, W.; Lu, S. Exosomal PD-L1 predicts response with immunotherapy in NSCLC patients. Clin. Exp. Immunol. 2022, 208, 316–322. [Google Scholar] [CrossRef]
  197. Shin, J.M.; Lee, C.H.; Son, S.; Kim, C.H.; Lee, J.A.; Ko, H.; Shin, S.; Song, S.H.; Park, S.S.; Bae, J.H.; et al. Sulfisoxazole Elicits Robust Antitumour Immune Response Along with Immune Checkpoint Therapy by Inhibiting Exosomal PD-L1. Adv. Sci. 2022, 9, e2103245. [Google Scholar] [CrossRef]
  198. Gong, Y.; Li, K.; Qin, Y.; Zeng, K.; Liu, J.; Huang, S.; Chen, Y.; Yu, H.; Liu, W.; Ye, L.; et al. Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma. Front. Oncol. 2021, 11, 711448. [Google Scholar] [CrossRef]
  199. Shimada, Y.; Matsubayashi, J.; Kudo, Y.; Maehara, S.; Takeuchi, S.; Hagiwara, M.; Kakihana, M.; Ohira, T.; Nagao, T.; Ikeda, N. Serum-derived exosomal PD-L1 expression to predict anti-PD-1 response and in patients with non-small cell lung cancer. Sci. Rep. 2021, 11, 7830. [Google Scholar] [CrossRef]
  200. Yin, Z.; Yu, M.; Ma, T.; Zhang, C.; Huang, S.; Karimzadeh, M.R.; Momtazi-Borojeni, A.A.; Chen, S. Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: A key role of exosomal PD-L1. J. Immunother. Cancer 2021, 9, e001698. [Google Scholar] [CrossRef]
  201. Pico de Coaña, Y.; Wolodarski, M.; van der Haar Àvila, I.; Nakajima, T.; Rentouli, S.; Lundqvist, A.; Masucci, G.; Hansson, J.; Kiessling, R. PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates. Oncoimmunology 2020, 9, 1786888. [Google Scholar] [CrossRef]
  202. Ando, K.; Hamada, K.; Shida, M.; Ohkuma, R.; Kubota, Y.; Horiike, A.; Matsui, H.; Ishiguro, T.; Hirasawa, Y.; Ariizumi, H.; et al. A high number of PD-L1+ CD14+ monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors. Cancer Immunol. Immunother. 2021, 70, 337–348. [Google Scholar] [CrossRef] [PubMed]
  203. Lee, C.H.; Bae, J.H.; Choe, E.J.; Park, J.M.; Park, S.S.; Cho, H.J.; Song, B.J.; Baek, M.C. Macitentan improves antitumor immune responses by inhibiting the secretion of tumor-derived extracellular vesicle PD-L1. Theranostics 2022, 12, 1971–1987. [Google Scholar] [CrossRef] [PubMed]
  204. Del Re, M.; van Schaik, R.H.N.; Fogli, S.; Mathijssen, R.H.J.; Cucchiara, F.; Capuano, A.; Scavone, C.; Jenster, G.W.; Danesi, R. Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: Applications for optimal use of anti-PD-1/PD-L1 axis inhibitors. Biochim. Biophys. Acta Rev. Cancer 2021, 1875, 188463. [Google Scholar] [CrossRef] [PubMed]
  205. Theodoraki, M.N.; Yerneni, S.S.; Hoffmann, T.K.; Gooding, W.E.; Whiteside, T.L. Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients. Clin. Cancer Res. 2018, 24, 896–905. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Chen, H.L.; Luo, Y.P.; Lin, M.W.; Peng, X.X.; Liu, M.L.; Wang, Y.C.; Li, S.J.; Yang, D.H.; Yang, Z.X. Serum exosomal miR-16-5p functions as a tumor inhibitor and a new biomarker for PD-L1 inhibitor-dependent immunotherapy in lung adenocarcinoma by regulating PD-L1 expression. Cancer Med. 2022, 11, 2627–2643. [Google Scholar] [CrossRef]
  207. Whiteside, T.L. The emerging role of plasma exosomes in diagnosis, prognosis and therapies of patients with cancer. Contemp. Oncol. 2018, 22, 38–40. [Google Scholar] [CrossRef]
  208. Muller, L.; Muller-Haegele, S.; Mitsuhashi, M.; Gooding, W.; Okada, H.; Whiteside, T.L. Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival. Oncoimmunology 2015, 4, e1008347. [Google Scholar] [CrossRef] [Green Version]
  209. Del Re, M.; Cucchiara, F.; Rofi, E.; Fontanelli, L.; Petrini, I.; Gri, N.; Pasquini, G.; Rizzo, M.; Gabelloni, M.; Belluomini, L.; et al. A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC. Cancer Immunol. Immunother. 2021, 70, 1667–1678. [Google Scholar] [CrossRef]
  210. Tang, Y.; Zhang, P.; Wang, Y.; Wang, J.; Su, M.; Wang, Y.; Zhou, L.; Zhou, J.; Xiong, W.; Zeng, Z.; et al. The Biogenesis, Biology, and Clinical Significance of Exosomal PD-L1 in Cancer. Front. Immunol. 2020, 11, 604. [Google Scholar] [CrossRef]
  211. Wang, M.; Zhai, X.; Li, J.; Guan, J.; Xu, S.; Li, Y.; Zhu, H. The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors. Front. Immunol. 2021, 12, 670391. [Google Scholar] [CrossRef]
  212. Cha, J.H.; Chan, L.C.; Li, C.W.; Hsu, J.L.; Hung, M.C. Mechanisms Controlling PD-L1 Expression in Cancer. Mol. Cell 2019, 76, 359–370. [Google Scholar] [CrossRef] [PubMed]
  213. Yi, M.; Niu, M.; Xu, L.; Luo, S.; Wu, K. Regulation of PD-L1 expression in the tumor microenvironment. J. Hematol. Oncol. 2021, 14, 10. [Google Scholar] [CrossRef] [PubMed]
  214. Fan, Y.; Che, X.; Qu, J.; Hou, K.; Wen, T.; Li, Z.; Li, C.; Wang, S.; Xu, L.; Liu, Y.; et al. Exosomal PD-L1 Retains Immunosuppressive Activity and is Associated with Gastric Cancer Prognosis. Ann. Surg. Oncol. 2019, 26, 3745–3755. [Google Scholar] [CrossRef] [PubMed]
  215. Liu, C.; Wang, Y.; Li, L.; He, D.; Chi, J.; Li, Q.; Wu, Y.; Zhao, Y.; Zhang, S.; Wang, L.; et al. Engineered extracellular vesicles and their mimetics for cancer immunotherapy. J. Control. Release 2022, 349, 679–698. [Google Scholar] [CrossRef]
  216. Yong, T.; Wei, Z.; Gan, L.; Yang, X. Extracellular Vesicle-Based Drug Delivery Systems for Enhanced Anti-Tumor Therapies through Modulating Cancer-Immunity Cycle. Adv. Mater. 2022, 20, e2201054. [Google Scholar] [CrossRef]
  217. Ding, Y.; Wang, L.; Li, H.; Miao, F.; Zhang, Z.; Hu, C.; Yu, W.; Tang, Q.; Shao, G. Application of lipid nanovesicle drug delivery system in cancer immunotherapy. J. Nanobiotechnol. 2022, 20, 214. [Google Scholar] [CrossRef]
  218. Calvo, V.; Izquierdo, M. T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy. Cells 2022, 11, 790. [Google Scholar] [CrossRef]
  219. Hao, Q.; Wu, Y.; Wu, Y.; Wang, P.; Vadgama, J.V. Tumor-Derived Exosomes in Tumor-Induced Immune Suppression. Int. J. Mol. Sci. 2022, 23, 1461. [Google Scholar] [CrossRef]
  220. Hosseini, R.; Sarvnaz, H.; Arabpour, M.; Ramshe, S.M.; Asef-Kabiri, L.; Yousefi, H.; Akbari, M.E.; Eskandari, N. Cancer exosomes and natural killer cells dysfunction: Biological roles, clinical significance and implications for immunotherapy. Mol. Cancer 2022, 21, 15. [Google Scholar] [CrossRef]
  221. Abu, N.; Rus Bakarurraini, N.A.A. The interweaving relationship between extracellular vesicles and T cells in cancer. Cancer Lett. 2022, 530, 1–7. [Google Scholar] [CrossRef]
  222. Shenoy, G.N.; Bhatta, M.; Bankert, R.B. Tumor-Associated Exosomes: A Potential Therapeutic Target for Restoring Anti-Tumor T Cell Responses in Human Tumor Microenvironments. Cells 2021, 10, 3155. [Google Scholar] [CrossRef] [PubMed]
  223. Ma, F.; Vayalil, J.; Lee, G.; Wang, Y.; Peng, G. Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment. J. Immunother. Cancer 2021, 9, e003217. [Google Scholar] [CrossRef] [PubMed]
  224. Wang, M.; Zhang, B. The Immunomodulation Potential of Exosomes in Tumor Microenvironment. J. Immunol. Res. 2021, 2021, 3710372. [Google Scholar] [CrossRef] [PubMed]
  225. Linder, M.; Pogge von Strandmann, E. The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells. Cancers 2021, 13, 4721. [Google Scholar] [CrossRef] [PubMed]
  226. Li, Q.; Cai, S.; Li, M.; Salma, K.I.; Zhou, X.; Han, F.; Chen, J.; Huyan, T. Tumor-Derived Extracellular Vesicles: Their Role in Immune Cells and Immunotherapy. Int. J. Nanomed. 2021, 16, 5395–5409. [Google Scholar] [CrossRef]
  227. Wu, F.; Xie, M.; Hun, M.; She, Z.; Li, C.; Luo, S.; Chen, X.; Wan, W.; Wen, C.; Tian, J. Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy. Front. Immunol. 2021, 12, 658698. [Google Scholar] [CrossRef]
  228. Hou, P.P.; Chen, H.Z. Extracellular vesicles in the tumor immune microenvironment. Cancer Lett. 2021, 516, 48–56. [Google Scholar] [CrossRef]
  229. Lipinski, S.; Tiemann, K. Extracellular Vesicles and Their Role in the Spatial and Temporal Expansion of Tumor-Immune Interactions. Int. J. Mol. Sci. 2021, 22, 3374. [Google Scholar] [CrossRef]
  230. Ayala-Mar, S.; Donoso-Quezada, J.; González-Valdez, J. Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy. J. Immunol. Res. 2021, 2021, 8839978. [Google Scholar] [CrossRef]
  231. Wang, L.; Sun, Z.; Wang, H. Extracellular vesicles and the regulation of tumor immunity: Current progress and future directions. J. Cell Biochem. 2021, 122, 760–769. [Google Scholar] [CrossRef]
  232. Srivastava, A.; Rathore, S.; Munshi, A.; Ramesh, R. Extracellular Vesicles in Oncology: From Immune Suppression to Immunotherapy. AAPS J. 2021, 23, 30. [Google Scholar] [CrossRef] [PubMed]
  233. Lucafò, M.; De Biasi, S.; Curci, D.; Norbedo, A.; Stocco, G.; Decorti, G. Extracellular Vesicles as Innovative Tools for Assessing Adverse Effects of Immunosuppressant Drugs. Curr. Med. Chem. 2022, 29, 3586–3600. [Google Scholar] [CrossRef] [PubMed]
  234. Negahdaripour, M.; Owji, H.; Eskandari, S.; Zamani, M.; Vakili, B.; Nezafat, N. Small extracellular vesicles (sEVs): Discovery, functions, applications, detection methods and various engineered forms. Expert Opin. Biol. Ther. 2021, 21, 371–394. [Google Scholar] [CrossRef] [PubMed]
  235. Jiang, X.C.; Zhang, T.; Gao, J.Q. The in vivo fate and targeting engineering of crossover vesicle-based gene delivery system. Adv. Drug Deliv. Rev. 2022, 187, 114324. [Google Scholar] [CrossRef]
  236. Raghav, A.; Jeong, G.B. A systematic review on the modifications of extracellular vesicles: A revolutionized tool of nano-biotechnology. J. Nanobiotechnol. 2021, 19, 459. [Google Scholar] [CrossRef]
  237. Kučuk, N.; Primožič, M.; Knez, Ž.; Leitgeb, M. Exosomes Engineering and Their Roles as Therapy Delivery Tools, Therapeutic Targets, and Biomarkers. Int. J. Mol. Sci. 2021, 22, 9543. [Google Scholar] [CrossRef]
  238. Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 2021, 11, 3183–3195. [Google Scholar] [CrossRef]
  239. Geng, T.; Pan, P.; Leung, E.; Chen, Q.; Chamley, L.; Wu, Z. Recent Advancement and Technical Challenges in Developing Small Extracellular Vesicles for Cancer Drug Delivery. Pharm. Res. 2021, 38, 179–197. [Google Scholar] [CrossRef]
  240. Xue, V.W.; Wong, S.C.C.; Song, G.; Cho, W.C.S. Promising RNA-based cancer gene therapy using extracellular vesicles for drug delivery. Expert Opin. Biol. Ther. 2020, 20, 767–777. [Google Scholar] [CrossRef]
  241. Jabłkowski, M.; Szemraj, M.; Oszajca, K.; Janiszewska, G.; Bartkowiak, J.; Szemraj, J. New type of BACE1 siRNA delivery to cells. Med. Sci. Monit. 2014, 20, 2598–2606. [Google Scholar] [CrossRef]
  242. Nawrot, B. Targeting BACE with small inhibitory nucleic acids—A future for Alzheimer’s disease therapy? Acta Biochim. Pol. 2004, 51, 431–444. [Google Scholar] [CrossRef] [Green Version]
  243. Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011, 29, 341–345. [Google Scholar] [CrossRef] [PubMed]
  244. Meldolesi, J. News about Therapies of Alzheimer’s Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments. Biomedicines 2022, 10, 105. [Google Scholar] [CrossRef] [PubMed]
  245. Zhang, Y.; Liu, Q.; Zhang, X.; Huang, H.; Tang, S.; Chai, Y.; Xu, Z.; Li, M.; Chen, X.; Liu, J.; et al. Recent advances in exosome-mediated nucleic acid delivery for cancer therapy. J. Nanobiotechnol. 2022, 20, 279. [Google Scholar] [CrossRef] [PubMed]
  246. Entezari, M.; Ghanbarirad, M.; Taheriazam, A.; Sadrkhanloo, M.; Zabolian, A.; Goharrizi, M.A.S.B.; Hushmandi, K.; Aref, A.R.; Ashrafizadeh, M.; Zarrabi, A.; et al. Long non-coding RNAs and exosomal lncRNAs: Potential functions in lung cancer progression, drug resistance and tumor microenvironment remodeling. Biomed. Pharmacother. 2022, 150, 112963. [Google Scholar] [CrossRef] [PubMed]
  247. Taghvimi, S.; Vakili, O.; Soltani Fard, E.; Khatami, S.H.; Karami, N.; Taheri-Anganeh, M.; Salehi, M.; Negahdari, B.; Ghasemi, H.; Movahedpour, A. Exosomal microRNAs and long noncoding RNAs: Novel mediators of drug resistance in lung cancer. J. Cell Physiol. 2022, 237, 2095–2106. [Google Scholar] [CrossRef]
  248. Sohrabi, B.; Dayeri, B.; Zahedi, E.; Khoshbakht, S.; Nezamabadi Pour, N.; Ranjbar, H.; Davari Nejad, A.; Noureddini, M.; Alani, B. Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther. 2022, 29, 1105–1116. [Google Scholar] [CrossRef]
  249. Sorop, A.; Constantinescu, D.; Cojocaru, F.; Dinischiotu, A.; Cucu, D.; Dima, S.O. Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma. Int. J. Mol. Sci. 2021, 22, 4997. [Google Scholar] [CrossRef]
  250. Mohammadi, R.; Hosseini, S.A.; Noruzi, S.; Ebrahimzadeh, A.; Sahebkar, A. Diagnostic and Therapeutic Applications of Exosome Nanovesicles in Lung Cancer: State-of-The-Art. Anticancer Agents Med. Chem. 2022, 22, 83–100. [Google Scholar] [CrossRef]
  251. Li, X.; Jiang, W.; Gan, Y.; Zhou, W. The Application of Exosomal MicroRNAs in the Treatment of Pancreatic Cancer and Its Research Progress. Pancreas 2021, 50, 12–16. [Google Scholar] [CrossRef]
  252. Mowla, M.; Hashemi, A. Functional roles of exosomal miRNAs in multi-drug resistance in cancer chemotherapeutics. Exp. Mol. Pathol. 2021, 118, 104592. [Google Scholar] [CrossRef] [PubMed]
  253. Nakase, I.; Kobayashi, N.B.; Takatani-Nakase, T.; Yoshida, T. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci. Rep. 2015, 5, 10300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  254. Nakagawa, Y.; Arafiles, J.V.V.; Kawaguchi, Y.; Nakase, I.; Hirose, H.; Futaki, S. Stearylated Macropinocytosis-Inducing Peptides Facilitating the Cellular Uptake of Small Extracellular Vesicles. Bioconjug. Chem. 2022, 33, 869–880. [Google Scholar] [CrossRef]
  255. Noguchi, K.; Obuki, M.; Sumi, H.; Klußmann, M.; Morimoto, K.; Nakai, S.; Hashimoto, T.; Fujiwara, D.; Fujii, I.; Yuba, E.; et al. Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery. Mol. Pharm. 2021, 18, 3290–3301. [Google Scholar] [CrossRef]
  256. Takenaka, T.; Nakai, S.; Katayama, M.; Hirano, M.; Ueno, N.; Noguchi, K.; Takatani-Nakase, T.; Fujii, I.; Kobayashi, S.S.; Nakase, I. Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells. Int. J. Pharm. 2019, 572, 118762. [Google Scholar] [CrossRef]
  257. Nakase, I.; Noguchi, K.; Aoki, A.; Takatani-Nakase, T.; Fujii, I.; Futaki, S. Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery. Sci. Rep. 2017, 7, 1991. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Nakase, I.; Noguchi, K.; Fujii, I.; Futaki, S. Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis. Sci. Rep. 2016, 6, 34937. [Google Scholar] [CrossRef] [Green Version]
  259. Nakase, I.; Takatani-Nakase, T. Exosomes: Breast cancer-derived extracellular vesicles; recent key findings and technologies in disease progression, diagnostics, and cancer targeting. Drug Metab. Pharmacokinet. 2022, 42, 100435. [Google Scholar] [CrossRef]
  260. Noguchi, K.; Hirano, M.; Hashimoto, T.; Yuba, E.; Takatani-Nakase, T.; Nakase, I. Effects of Lyophilization of Arginine-rich Cell-penetrating Peptide-modified Extracellular Vesicles on Intracellular Delivery. Anticancer Res. 2019, 39, 6701–6709. [Google Scholar] [CrossRef]
  261. Siddiqui, H.; Yevstigneyev, N.; Madani, G.; McCormick, S. Approaches to Visualising Endocytosis of LDL-Related Lipoproteins. Biomolecules 2022, 12, 158. [Google Scholar] [CrossRef]
  262. Varma, S.; Dey, S.; Palanisamy, D. Cellular Uptake Pathways of Nanoparticles: Process of Endocytosis and Factors Affecting their Fate. Curr. Pharm. Biotechnol. 2022, 23, 679–706. [Google Scholar] [CrossRef]
  263. Cooke, L.D.F.; Tumbarello, D.A.; Harvey, N.C.; Sethi, J.K.; Lewis, R.M.; Cleal, J.K. Endocytosis in the placenta: An undervalued mediator of placental transfer. Placenta 2021, 113, 67–73. [Google Scholar] [CrossRef] [PubMed]
  264. Vieira, N.; Rito, T.; Correia-Neves, M.; Sousa, N. Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease. Mol. Neurobiol. 2021, 58, 4070–4106. [Google Scholar] [CrossRef] [PubMed]
  265. Renard, H.F.; Boucrot, E. Unconventional endocytic mechanisms. Curr. Opin. Cell Biol. 2021, 71, 120–129. [Google Scholar] [CrossRef] [PubMed]
  266. Mushtaq, A.; Li, L.A.A.; Grøndahl, L. Chitosan Nanomedicine in Cancer Therapy: Targeted Delivery and Cellular Uptake. Macromol. Biosci. 2021, 21, e2100005. [Google Scholar] [CrossRef] [PubMed]
  267. Kahlhofer, J.; Leon, S.; Teis, D.; Schmidt, O. The α-arrestin family of ubiquitin ligase adaptors links metabolism with selective endocytosis. Biol. Cell 2021, 113, 183–219. [Google Scholar] [CrossRef] [PubMed]
  268. Luk, B.T.; Zhang, L. Cell membrane-camouflaged nanoparticles for drug delivery. J. Control. Release 2015, 220, 600–607. [Google Scholar] [CrossRef] [Green Version]
  269. Lee, N.H.; You, S.; Taghizadeh, A.; Taghizadeh, M.; Kim, H.S. Cell Membrane-Cloaked Nanotherapeutics for Targeted Drug Delivery. Int. J. Mol. Sci. 2022, 23, 2223. [Google Scholar] [CrossRef]
  270. Smith, S.M.; Smith, C.J. Capturing the mechanics of clathrin-mediated endocytosis. Curr. Opin. Struct. Biol. 2022, 75, 102427. [Google Scholar] [CrossRef]
  271. Shi, R.; Hou, L.; Wei, L.; Liu, J. Involvement of adaptor proteins in clathrin-mediated endocytosis of virus entry. Microb. Pathog. 2021, 161, 105278. [Google Scholar] [CrossRef]
  272. Redlingshöfer, L.; Brodsky, F.M. Antagonistic regulation controls clathrin-mediated endocytosis: AP2 adaptor facilitation vs restraint from clathrin light chains. Cells Dev. 2021, 168, 203714. [Google Scholar] [CrossRef] [PubMed]
  273. Moo, E.V.; van Senten, J.R.; Bräuner-Osborne, H.; Møller, T.C. Arrestin-Dependent and -Independent Internalization of G Protein-Coupled Receptors: Methods, Mechanisms, and Implications on Cell Signaling. Mol. Pharmacol. 2021, 99, 242–255. [Google Scholar] [CrossRef] [PubMed]
  274. Li, W.; Hu, J.; Li, X.; Lu, Z.; Li, X.; Wang, C.; Yu, S. Receptor-Dependent Endocytosis Mediates α-Synuclein Oligomer Transport into Red Blood Cells. Front. Aging Neurosci. 2022, 14, 899892. [Google Scholar] [CrossRef] [PubMed]
  275. Singh, M.; Jadhav, H.R.; Bhatt, T. Dynamin Functions and Ligands: Classical Mechanisms Behind. Mol. Pharmacol. 2017, 91, 123–134. [Google Scholar] [CrossRef] [Green Version]
  276. Wolfe, B.L.; Trejo, J. Clathrin-dependent mechanisms of G protein-coupled receptor endocytosis. Traffic 2007, 8, 462–470. [Google Scholar] [CrossRef]
  277. Rejman, J.; Oberle, V.; Zuhorn, I.S.; Hoekstra, D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem. J. 2004, 377, 159–169. [Google Scholar] [CrossRef]
  278. Langston Suen, W.L.; Chau, Y. Size-dependent internalisation of folate-decorated nanoparticles via the pathways of clathrin and caveolae-mediated endocytosis in ARPE-19 cells. J. Pharm. Pharmacol. 2014, 66, 564–573. [Google Scholar] [CrossRef]
  279. Hackett, B.A.; Cherry, S. Flavivirus internalization is regulated by a size-dependent endocytic pathway. Proc. Natl. Acad. Sci. USA 2018, 115, 4246–4251. [Google Scholar] [CrossRef] [Green Version]
  280. Ueda, Y.; Sato, M. Cell membrane dynamics induction using optogenetic tools. Biochem. Biophys. Res. Commun. 2018, 506, 387–393. [Google Scholar] [CrossRef]
  281. Gozzelino, L.; De Santis, M.C.; Gulluni, F.; Hirsch, E.; Martini, M. PI(3, 4)P2 Signaling in Cancer and Metabolism. Front. Oncol. 2020, 10, 360. [Google Scholar] [CrossRef]
  282. Liu, H.; Qian, F. Exploiting macropinocytosis for drug delivery into KRAS mutant cancer. Theranostics 2022, 12, 1321–1332. [Google Scholar] [CrossRef] [PubMed]
  283. Liu, X.; Ghosh, D. Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis. Int. J. Nanomed. 2019, 14, 6589–6600. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  284. Michalopoulou, E.; Auciello, F.R.; Bulusu, V.; Strachan, D.; Campbell, A.D.; Tait-Mulder, J.; Karim, S.A.; Morton, J.P.; Sansom, O.J.; Kamphorst, J.J. Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition. Cell Rep. 2020, 30, 2729–2742.e4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  285. Zhang, M.S.; Cui, J.D.; Lee, D.; Yuen, V.W.; Chiu, D.K.; Goh, C.C.; Cheu, J.W.; Tse, A.P.; Bao, M.H.; Wong, B.P.Y.; et al. Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer. Nat. Commun. 2022, 13, 954. [Google Scholar] [CrossRef]
  286. Recouvreux, M.V.; Commisso, C. Macropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer. Front. Endocrinol. 2017, 8, 261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. Commisso, C. The pervasiveness of macropinocytosis in oncological malignancies. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2019, 374, 20180153. [Google Scholar] [CrossRef] [Green Version]
  288. Sutton, M.N.; Gammon, S.T.; Muzzioli, R.; Pisaneschi, F.; Radaram, B.; Yang, P.; Piwnica-Worms, D. RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging. Mol. Imaging Biol. 2022, 24, 498–509. [Google Scholar] [CrossRef]
  289. Sheng, W.; Geng, J.; Li, L.; Shang, Y.; Jiang, M.; Zhen, Y. An albumin-binding domain and targeting peptide-based recombinant protein and its enediyne-integrated analogue exhibit directional delivery and potent inhibitory activity on pancreatic cancer with K-ras mutation. Oncol. Rep. 2020, 43, 851–863. [Google Scholar] [CrossRef]
  290. Thu, P.M.; Zheng, Z.G.; Zhou, Y.P.; Wang, Y.Y.; Zhang, X.; Jing, D.; Cheng, H.M.; Li, J.; Li, P.; Xu, X. Phellodendrine chloride suppresses proliferation of KRAS mutated pancreatic cancer cells through inhibition of nutrients uptake via macropinocytosis. Eur. J. Pharmacol. 2019, 850, 23–34. [Google Scholar] [CrossRef]
  291. Zhang, Y.; Wei, Y.; Liu, P.; Zhang, X.; Xu, Z.; Tan, X.; Chen, M.; Wang, J. ICP-MS and Photothermal Dual-Readout Assay for Ultrasensitive and Point-of-Care Detection of Pancreatic Cancer Exosomes. Anal. Chem. 2021, 93, 11540–11546. [Google Scholar] [CrossRef]
  292. Buscail, E.; Alix-Panabières, C.; Quincy, P.; Cauvin, T.; Chauvet, A.; Degrandi, O.; Caumont, C.; Verdon, S.; Lamrissi, I.; Moranvillier, I.; et al. High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery. Cancers 2019, 11, 1656. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  293. Xiao, D.; Dong, Z.; Zhen, L.; Xia, G.; Huang, X.; Wang, T.; Guo, H.; Yang, B.; Xu, C.; Wu, W.; et al. Combined Exosomal GPC1, CD82, and Serum CA19-9 as Multiplex Targets: A Specific, Sensitive, and Reproducible Detection Panel for the Diagnosis of Pancreatic Cancer. Mol. Cancer Res. 2020, 18, 300–310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  294. Buscail, E.; Chauvet, A.; Quincy, P.; Degrandi, O.; Buscail, C.; Lamrissi, I.; Moranvillier, I.; Caumont, C.; Verdon, S.; Brisson, A.; et al. CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma. Transl. Oncol. 2019, 12, 1395–1403. [Google Scholar] [CrossRef] [PubMed]
  295. Zanetti-Domingues, L.C.; Bonner, S.E.; Iyer, R.S.; Martin-Fernandez, M.L.; Huber, V. Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer. Cells 2020, 9, 2639. [Google Scholar] [CrossRef] [PubMed]
  296. Gonda, A.; Kabagwira, J.; Senthil, G.N.; Wall, N.R. Internalization of Exosomes through Receptor-Mediated Endocytosis. Mol. Cancer Res. 2019, 17, 337–347. [Google Scholar] [CrossRef] [Green Version]
  297. Ramos-Zaldívar, H.M.; Polakovicova, I.; Salas-Huenuleo, E.; Corvalán, A.H.; Kogan, M.J.; Yefi, C.P.; Andia, M.E. Extracellular vesicles through the blood-brain barrier: A review. Fluids Barriers CNS 2022, 19, 60. [Google Scholar] [CrossRef]
  298. Nakase, I. Biofunctional Peptide-Modified Extracellular Vesicles Enable Effective Intracellular Delivery via the Induction of Macropinocytosis. Processes 2021, 9, 224. [Google Scholar] [CrossRef]
  299. Sun, W.; Ren, Y.; Lu, Z.; Zhao, X. The potential roles of exosomes in pancreatic cancer initiation and metastasis. Mol. Cancer 2020, 19, 135. [Google Scholar] [CrossRef]
  300. Beit-Yannai, E.; Tabak, S.; Stamer, W.D. Physical exosome:exosome interactions. J. Cell Mol. Med. 2018, 22, 2001–2006. [Google Scholar] [CrossRef] [Green Version]
  301. Midekessa, G.; Godakumara, K.; Ord, J.; Viil, J.; Lättekivi, F.; Dissanayake, K.; Kopanchuk, S.; Rinken, A.; Andronowska, A.; Bhattacharjee, S.; et al. Zeta Potential of Extracellular Vesicles: Toward Understanding the Attributes that Determine Colloidal Stability. ACS Omega 2020, 5, 16701–16710. [Google Scholar] [CrossRef]
  302. Kesimer, M.; Gupta, R. Physical characterization and profiling of airway epithelial derived exosomes using light scattering. Methods 2015, 87, 59–63. [Google Scholar] [CrossRef] [Green Version]
  303. Yang, Y.; Shen, G.; Wang, H.; Li, H.; Zhang, T.; Tao, N.; Ding, X.; Yu, H. Interferometric plasmonic imaging and detection of single exosomes. Proc. Natl. Acad. Sci. USA 2018, 115, 10275–10280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  304. Pedrioli, G.; Paganetti, P. Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside. Front. Cell Dev. Biol. 2021, 8, 595515. [Google Scholar] [CrossRef] [PubMed]
  305. Kamerkar, S.; LeBleu, V.S.; Sugimoto, H.; Yang, S.; Ruivo, C.F.; Melo, S.A.; Lee, J.J.; Kalluri, R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017, 546, 498–503. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  306. Yuan, F.; Sun, M.; Liu, Z.; Liu, H.; Kong, W.; Wang, R.; Qian, F. Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer. Theranostics 2022, 12, 1061–1073. [Google Scholar] [CrossRef]
  307. Mendt, M.; Kamerkar, S.; Sugimoto, H.; McAndrews, K.M.; Wu, C.C.; Gagea, M.; Yang, S.; Blanko, E.V.R.; Peng, Q.; Ma, X.; et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018, 3, e99263. [Google Scholar] [CrossRef]
  308. Zhao, Z.; Zhao, G.; Yang, S.; Zhu, S.; Zhang, S.; Li, P. The significance of exosomal RNAs in the development, diagnosis, and treatment of pancreatic cancer. Cancer Cell Int. 2021, 21, 364. [Google Scholar] [CrossRef]
  309. Jing, C.; Cao, H.; Qin, X.; Yu, S.; Wu, J.; Wang, Z.; Ma, R.; Feng, J. Exosome-mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR-21. Oncol. Lett. 2018, 15, 9811–9817. [Google Scholar] [CrossRef]
  310. Srivastava, A.; Amreddy, N.; Babu, A.; Panneerselvam, J.; Mehta, M.; Muralidharan, R.; Chen, A.; Zhao, Y.D.; Razaq, M.; Riedinger, N.; et al. Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci. Rep. 2016, 6, 38541. [Google Scholar] [CrossRef] [Green Version]
  311. Rizwan, M.N.; Ma, Y.; Nenkov, M.; Jin, L.; Schröder, D.C.; Westermann, M.; Gaßler, N.; Chen, Y. Tumor-derived exosomes: Key players in non-small cell lung cancer metastasis and their implication for targeted therapy. Mol. Carcinog. 2022, 61, 269–280. [Google Scholar] [CrossRef]
  312. Nakase, I. Development of Intracellular Delivery System Based on Biofunctional Peptide–modified Exosome. Membrane 2016, 41, 209–214. [Google Scholar] [CrossRef]
  313. Sancho-Albero, M.; Sebastián, V.; Sesé, J.; Pazo-Cid, R.; Mendoza, G.; Arruebo, M.; Martín-Duque, P.; Santamaría, J. Isolation of exosomes from whole blood by a new microfluidic device: Proof of concept application in the diagnosis and monitoring of pancreatic cancer. J. Nanobiotechnol. 2020, 18, 150. [Google Scholar] [CrossRef] [PubMed]
  314. Nakase, I.; Akita, H.; Kogure, K.; Gräslund, A.; Langel, U.; Harashima, H.; Futaki, S. Efficient intracellular delivery of nucleic acid pharmaceuticals using cell-penetrating peptides. Acc. Chem. Res. 2012, 45, 1132–1139. [Google Scholar] [CrossRef]
  315. Nakase, I.; Ueno, N.; Katayama, M.; Noguchi, K.; Takatani-Nakase, T.; Kobayashi, N.B.; Yoshida, T.; Fujii, I.; Futaki, S. Receptor clustering and activation by multivalent interaction through recognition peptides presented on exosomes. Chem. Commun. 2016, 53, 317–320. [Google Scholar] [CrossRef] [PubMed]
  316. Futaki, S.; Nakase, I. Cell-Surface Interactions on Arginine-Rich Cell-Penetrating Peptides Allow for Multiplex Modes of Internalization. Acc. Chem. Res. 2017, 50, 2449–2456. [Google Scholar] [CrossRef]
  317. Nakase, I.; Osaki, K.; Tanaka, G.; Utani, A.; Futaki, S. Molecular interplays involved in the cellular uptake of octaarginine on cell surfaces and the importance of syndecan-4 cytoplasmic V domain for the activation of protein kinase Cα. Biochem. Biophys. Res. Commun. 2014, 446, 857–862. [Google Scholar] [CrossRef]
  318. Albrecht, L.V.; Tejeda-Muñoz, N.; Bui, M.H.; Cicchetto, A.C.; Di Biagio, D.; Colozza, G.; Schmid, E.; Piccolo, S.; Christofk, H.R.; De Robertis, E.M. GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery. Cell Rep. 2020, 32, 107973. [Google Scholar] [CrossRef]
  319. Reggiori, F.; Gabius, H.J.; Aureli, M.; Römer, W.; Sonnino, S.; Eskelinen, E.L. Glycans in autophagy, endocytosis and lysosomal functions. Glycoconj. J. 2021, 38, 625–647. [Google Scholar] [CrossRef]
  320. Kobayashi, S.; Nakase, I.; Kawabata, N.; Yu, H.H.; Pujals, S.; Imanishi, M.; Giralt, E.; Futaki, S. Cytosolic targeting of macromolecules using a pH-dependent fusogenic peptide in combination with cationic liposomes. Bioconjug. Chem. 2009, 20, 953–959. [Google Scholar] [CrossRef]
  321. Nakase, I.; Kogure, K.; Harashima, H.; Futaki, S. Application of a fusiogenic peptide GALA for intracellular delivery. Methods Mol. Biol. 2011, 683, 525–533. [Google Scholar] [CrossRef]
  322. Nakase, I.; Futaki, S. Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Sci. Rep. 2015, 5, 10112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  323. Matsuzaka, Y.; Tanihata, J.; Komaki, H.; Ishiyama, A.; Oya, Y.; Rüegg, U.; Takeda, S.I.; Hashido, K. Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice. PLoS ONE 2016, 11, e0167811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  324. Sivanantham, A.; Jin, Y. Impact of Storage Conditions on EV Integrity/Surface Markers and Cargos. Life 2022, 12, 697. [Google Scholar] [CrossRef] [PubMed]
  325. Wu, J.Y.; Li, Y.J.; Hu, X.B.; Huang, S.; Xiang, D.X. Preservation of small extracellular vesicles for functional analysis and therapeutic applications: A comparative evaluation of storage conditions. Drug Deliv. 2021, 28, 162–170. [Google Scholar] [CrossRef] [PubMed]
  326. Zhang, Y.; Bi, J.; Huang, J.; Tang, Y.; Du, S.; Li, P. Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications. Int. J. Nanomed. 2020, 15, 6917–6934. [Google Scholar] [CrossRef] [PubMed]
  327. Jeyaram, A.; Jay, S.M. Preservation and Storage Stability of Extracellular Vesicles for Therapeutic Applications. AAPS J. 2017, 20, 1. [Google Scholar] [CrossRef]
  328. Görgens, A.; Corso, G.; Hagey, D.W.; Jawad Wiklander, R.; Gustafsson, M.O.; Felldin, U.; Lee, Y.; Bostancioglu, R.B.; Sork, H.; Liang, X.; et al. Identification of storage conditions stabilizing extracellular vesicles preparations. J. Extracell. Vesicles 2022, 11, e12238. [Google Scholar] [CrossRef]
  329. Deville, S.; Berckmans, P.; Van Hoof, R.; Lambrichts, I.; Salvati, A.; Nelissen, I. Comparison of extracellular vesicle isolation and storage methods using high-sensitivity flow cytometry. PLoS ONE 2021, 16, e0245835. [Google Scholar] [CrossRef]
  330. Tsuchiya, A.; Terai, S.; Horiguchi, I.; Homma, Y.; Saito, A.; Nakamura, N.; Sato, Y.; Ochiya, T.; Kino-Oka, M.; Working Group of Attitudes for Preparation and Treatment of Exosomes of Japanese Society of Regenerative Medicine. Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan. Regen. Ther. 2022, 21, 19–24. [Google Scholar] [CrossRef]
  331. Gimona, M.; Brizzi, M.F.; Choo, A.B.H.; Dominici, M.; Davidson, S.M.; Grillari, J.; Hermann, D.M.; Hill, A.F.; de Kleijn, D.; Lai, R.C.; et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy 2021, 23, 373–380. [Google Scholar] [CrossRef]
  332. Umezu, T.; Takanashi, M.; Murakami, Y.; Ohno, S.I.; Kanekura, K.; Sudo, K.; Nagamine, K.; Takeuchi, S.; Ochiya, T.; Kuroda, M. Acerola exosome-like nanovesicles to systemically deliver nucleic acid medicine via oral administration. Mol. Ther. Methods Clin. Dev. 2021, 21, 199–208. [Google Scholar] [CrossRef]
  333. Fujita, Y.; Kadota, T.; Araya, J.; Ochiya, T.; Kuwano, K. Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases. J. Clin. Med. 2018, 7, 355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  334. Urabe, F.; Kosaka, N.; Kimura, T.; Egawa, S.; Ochiya, T. Extracellular vesicles: Toward a clinical application in urological cancer treatment. Int. J. Urol. 2018, 25, 533–543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  335. Liew, L.C.; Katsuda, T.; Gailhouste, L.; Nakagama, H.; Ochiya, T. Mesenchymal stem cell-derived extracellular vesicles: A glimmer of hope in treating Alzheimer’s disease. Int. Immunol. 2017, 29, 11–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  336. Liu, X.; Zhang, G.; Yu, T.; He, J.; Liu, J.; Chai, X.; Zhao, G.; Yin, D.; Zhang, C. Exosomes deliver lncRNA DARS-AS1 siRNA to inhibit chronic unpredictable mild stress-induced TNBC metastasis. Cancer Lett. 2022, 543, 215781. [Google Scholar] [CrossRef] [PubMed]
  337. Shan, S.; Chen, J.; Sun, Y.; Wang, Y.; Xia, B.; Tan, H.; Pan, C.; Gu, G.; Zhong, J.; Qing, G.; et al. Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy. Adv. Sci. 2022, 9, e2200353. [Google Scholar] [CrossRef] [PubMed]
  338. Subhan, M.A.; Torchilin, V.P. siRNA based drug design, quality, delivery and clinical translation. Nanomedicine 2020, 29, 102239. [Google Scholar] [CrossRef]
  339. Zhang, Q.; Zhang, H.; Ning, T.; Liu, D.; Deng, T.; Liu, R.; Bai, M.; Zhu, K.; Li, J.; Fan, Q.; et al. Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer. Int. J. Nanomed. 2020, 15, 2323–2335. [Google Scholar] [CrossRef] [Green Version]
  340. Zhupanyn, P.; Ewe, A.; Büch, T.; Malek, A.; Rademacher, P.; Müller, C.; Reinert, A.; Jaimes, Y.; Aigner, A. Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo. J. Control. Release 2020, 319, 63–76. [Google Scholar] [CrossRef]
  341. Nishida-Aoki, N.; Tominaga, N.; Takeshita, F.; Sonoda, H.; Yoshioka, Y.; Ochiya, T. Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis. Mol. Ther. 2017, 25, 181–191. [Google Scholar] [CrossRef]
  342. Zafarani, A.; Taghavi-Farahabadi, M.; Razizadeh, M.H.; Amirzargar, M.R.; Mansouri, M.; Mahmoudi, M. The Role of NK Cells and Their Exosomes in Graft Versus Host Disease and Graft Versus Leukemia. Stem Cell Rev. Rep. 2022, in press. [Google Scholar] [CrossRef]
  343. Fujii, S.; Miura, Y. Immunomodulatory and regenerative effects of MSC-derived extracellular vesicles to treat acute GVHD. Stem Cells 2022, in press. [Google Scholar] [CrossRef]
  344. Fujii, S.; Miura, Y.; Fujishiro, A.; Shindo, T.; Shimazu, Y.; Hirai, H.; Tahara, H.; Takaori-Kondo, A.; Ichinohe, T.; Maekawa, T. Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations. Stem Cells 2018, 36, 434–445. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Exosomal PD-L1 in tumour growth and anti-PD-1/PD-L1 therapy. Exosomal PD-L1 secreted by tumour cells is leading to enhancement of tumour growth by reduction of T cell activity and inhibition of cytokine production, including IFN-γ and IL2, and limit effectiveness of anti-PD-1/PD-L1 therapy through binding to antibodies. On the other hand, elimination of the exosomal PD-L1 improves anti-PD-1/PD-L1 therapy.
Figure 1. Exosomal PD-L1 in tumour growth and anti-PD-1/PD-L1 therapy. Exosomal PD-L1 secreted by tumour cells is leading to enhancement of tumour growth by reduction of T cell activity and inhibition of cytokine production, including IFN-γ and IL2, and limit effectiveness of anti-PD-1/PD-L1 therapy through binding to antibodies. On the other hand, elimination of the exosomal PD-L1 improves anti-PD-1/PD-L1 therapy.
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Figure 2. Uptake mechanisms for the transport of EVs. Macropinocytosis is characterized by signal transduction involving the activation of the small G-protein Rac, which leads to polymerization of the actin backbone and formation of lamellipodia in the plasma membrane. Utilizing the lamellipodia structure of the plasma membrane, cells usually surround the extracellular fluid with a size of more than 1 μm, eventually forming vacuoles and taking them into the cell. Clathrin-mediated endocytosis involves five steps, including depression formation of membrane, accumulation of cargo, membrane encapsulation (formation of clathrin-coated pits), cutting, and uncoating, to deliver membrane vesicles containing cargo into the cell. The formation of caveolar endocytic vesicles requires the oligomerization of caveolin, which leads to the formation of caveolin-rich microdomains in the plasma membrane. ILVs: intralumenal vesicles.
Figure 2. Uptake mechanisms for the transport of EVs. Macropinocytosis is characterized by signal transduction involving the activation of the small G-protein Rac, which leads to polymerization of the actin backbone and formation of lamellipodia in the plasma membrane. Utilizing the lamellipodia structure of the plasma membrane, cells usually surround the extracellular fluid with a size of more than 1 μm, eventually forming vacuoles and taking them into the cell. Clathrin-mediated endocytosis involves five steps, including depression formation of membrane, accumulation of cargo, membrane encapsulation (formation of clathrin-coated pits), cutting, and uncoating, to deliver membrane vesicles containing cargo into the cell. The formation of caveolar endocytic vesicles requires the oligomerization of caveolin, which leads to the formation of caveolin-rich microdomains in the plasma membrane. ILVs: intralumenal vesicles.
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Matsuzaka, Y.; Yashiro, R. Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery. Int. J. Mol. Sci. 2022, 23, 12971. https://doi.org/10.3390/ijms232112971

AMA Style

Matsuzaka Y, Yashiro R. Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery. International Journal of Molecular Sciences. 2022; 23(21):12971. https://doi.org/10.3390/ijms232112971

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Matsuzaka, Yasunari, and Ryu Yashiro. 2022. "Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery" International Journal of Molecular Sciences 23, no. 21: 12971. https://doi.org/10.3390/ijms232112971

APA Style

Matsuzaka, Y., & Yashiro, R. (2022). Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery. International Journal of Molecular Sciences, 23(21), 12971. https://doi.org/10.3390/ijms232112971

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