TABLE 2.
Eligible studies included in the systematic review showing the application of extracellular vesicles (EVs) as diagnostic biomarkers and therapeutics or both in neurodegenerative disease.
| S. No. | Author, Year, Country | Application of the study (Therapeutics/Diagnostic/Both) | Highlights of the study | References |
| 1 | Candelario and Steindler, 2014, USA | Both | Evidence is mounting that EVs can transport mRNAs, miRNAs, non-coding RNAs, and proteins, including those linked to neurodegenerative diseases and cancer, which can then be exchanged between cells. EVs have been found to carry proteins that are prone to aggregation, which is a feature of many neurodegenerative disorders. Patient-specific EVs have the potential to be used as therapeutics in new regenerative medicine protocols for both neurodegenerative diseases. |
Candelario and Steindler, 2014 |
| 2 | Izadpanah et al., 2018, Iran | Both | Because EVs are involved in intercellular communication and a variety of biological processes such as immune response modulation, signal transduction, and transport of low immunogenic genetic materials, they have recently been investigated for the delivery of therapeutic molecules such as siRNAs and drugs in the treatment of diseases. Furthermore, because EV components reflect the physiological state of the cells and tissues that produce them, they can be used as biomarkers for the early detection of various diseases. |
Izadpanah et al., 2018 |
| 3 | Hill, 2019, Australia | Both | Altered genetic cargos, usually in the form of miRNAs, have also been found in EVs patients with these diseases, implying that EVs could be a source of disease biomarkers. Because EVs have been identified as a key pathological contributor to neurological conditions, they will serve as a novel therapeutic target. |
Hill, 2019 |
| 4 | Abdel-Haq, 2020, Italy | Both | Neural-derived blood EVs may be the best strategy for specific, dependable, and early diagnosis of neurodegenerative diseases. EVs have the potential to perform liquid brain biopsy using NDBEVs for early diagnosis and treatment of neurodegenerative diseases. |
Abdel-Haq, 2020 |
| 5 | Shaimardanova et al., 2020, Russia | Both | The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system, and molecular analysis of extracellular vesicle content aids in the development of non-invasive methods for diagnosing many central nervous system diseases. Extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain due to their nano size, biosafety, ability to cross the blood-brain barrier, the possibility of targeted delivery, and the lack of an immune response. |
Shaimardanova et al., 2020 |
| 6 | Jin et al., 2021, China | Both | EVs have been shown to transport molecules associated with diseases across the blood-brain barrier (BBB), allowing them to be detected in the blood. Because of this distinguishing feature, they have the potential to serve as diagnostic biomarkers for neurological disorders. EVs derived from mesenchymal stem cells (MSCs) have neurorestorative properties. |
Jin et al., 2021 |
| 7 | Yuan et al., 2019, China | Both | EVs contain proteins linked to the pathogenesis of neurodegenerative diseases (NDs), such as -synuclein (-syn) and tau proteins, implying potential roles for EVs as biomarkers and carriers of drugs and other therapeutic molecules that can cross the blood-brain barrier to treat NDs. | Yuan et al., 2019 |
| 8 | Upadhya and Shetty, 2021, USA | Both | EVs are also found in cerebrospinal fluid (CSF) and circulating blood, and their identification could lead to the identification of biomarkers linked to specific neurodegenerative diseases. EVs secreted by various stem/progenitor cells contain therapeutic miRNAs and proteins that have shown promise in alleviating symptoms and slowing the progression of neurodegenerative diseases. |
Upadhya and Shetty, 2021 |
| 9 | Vassileff et al., 2020, Australia | Both | EVs and miRNAs have biomarker potential for early diagnosis of these diseases, with stem cell-derived EVs and those generated with exogenous assistance having the most therapeutic potential. | Vassileff et al., 2020 |
| 10 | You and Ikezu, 2019, USA | Both | EVs have the potential to be used as both a diagnostic marker and a therapeutic agent in neurodegenerative disorders. | You and Ikezu, 2019 |
| 11 | Manu et al., 2021, Japan | Both | Circulating EVs can be used as a biomarker to monitor MS disease progression and activity, as well as therapeutic reagents or therapy targets. | Manu et al., 2021 |
| 12 | Zhao et al., 2021, China | Both | Astrocytes-derived EVs contain a high concentration of proteins and nucleic acids that are beneficial to neurons, such as CRYAB and PrP. AEV contents as diagnostic biomarkers for a variety of neurological diseases, identification of key targets for manipulating AEV release, and clarification of various AEV subtypes and their functions |
Zhao et al., 2021 |
| 13 | Anakor et al., 2021, UK | Both | Exosomes are suspected of propagating toxic proteins in neurodegenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, or Parkinson’s disease. ALS exosomes can be used as a biomarker as well as a therapeutic. |
Anakor et al., 2021 |
| 14 | Lee and Kim, 2017, Republic of Korea | Both | EVs are responsible for the spread of key pathogenic proteins involved in the pathogenesis of amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative disorders. EVs have an advantage over other synthetic drug delivery systems or cell therapy in that they can cross biological barriers such as the blood brain barrier (BBB), modulate inflammation and immune responses, have a longer biodistribution time, and are tumorigenic. EVs have the potential to be used as both a therapeutic and a biomarker in neurodegenerative diseases. |
Lee and Kim, 2017 |
| 15 | Mäger et al., 2020, UK | Both | EVs can be used as diagnostic biomarkers and therapeutics in normal CNS physiology and neurodegenerative diseases, with a focus on Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and prion diseases. | Mäger et al., 2020 |
| 16 | Zhang et al., 2021, China | Both | Exosomes play a critical role in CNS cell-cell communication. Exosomes play a dual role in the pathological process of Alzheimer’s disease. Exosomes show promise in the diagnosis and treatment of Alzheimer’s disease. |
Zhang et al., 2021 |
| 17 | Zhang et al., 2019, China | Both | Exosomes are linked to the transmission of disease-related misfolded proteins (such as -synuclein, tau, amyloid -protein, and others) in several neurodegenerative diseases. Exosomes can be used as biomarkers and drug delivery vehicles in the diagnosis and treatment of neurodegenerative diseases. |
Zhang et al., 2019 |
| 18 | Jan et al., 2017, India | Both | EVs have been linked to the transport of various cellular entities across the blood-brain barrier (BBB) and may be useful for delivering drugs and other therapeutic molecules to the brain. EVs also aid in the delivery of disease-causing entities such as prions, -syn, and tau, allowing them to spread to unaffected areas and accelerate the progression of neurodegenerative diseases. |
Jan et al., 2017 |
| 19 | Picca et al., 2022, Italy | Both | The use of EVs for diagnostic and therapeutic purposes may provide unprecedented opportunities for developing personalized approaches. | Picca et al., 2022 |
| 20 | Jiang et al., 2019, China | Both | EVs shed light on potential treatments for other neurodegenerative diseases. Detection of p-tau and A1–42 can improve diagnostic sensitivity and specificity because these two potential biomarkers are more likely to be delivered to extracellular fluids by exosomes in AD. |
Jiang et al., 2019 |
| 21 | Gagliardi et al., 2021, Italy | Both | Because EVs can enter the systemic circulation and are easily detected in patients’ biological fluids, they have sparked widespread interest as diagnostic and prognostic biomarkers, as well as valuable tools for understanding disease pathogenesis. EVs in amyotrophic lateral sclerosis patients’ blood and cerebrospinal fluid (CSF), implying their potential use in diagnosis and prognosis. EVs may also be used to treat amyotrophic lateral sclerosis. |
Gagliardi et al., 2021 |
| 22 | D’Anca et al., 2021, Italy | Both | EVs contain bioactive molecules (nucleic acids, proteins, and lipids) that affect the recipient cell’s genotype and phenotype. This means that not only EVs themselves, but also their content, may reveal new candidate disease biomarkers and/or therapeutic agents. | D’Anca et al., 2021 |
| 23 | Toshihide, 2021, Japan | Both | EVs would shed light not only on potential therapeutic targets for neurodegenerative diseases, but also on the development of EV-based biomarkers for disease detection. | Toshihide, 2021 |
| 24 | Yin et al., 2020, China | Both | Exosomes could aid in the early detection of Alzheimer’s disease and the identification of new therapeutic targets. | Yin et al., 2020 |
| 25 | Cui et al., 2021, China | Both | Exosomal miRNA content has the potential to be used as a diagnostic and therapeutic tool in neurodegenerative disease. | Cui et al., 2021 |
| 26 | He et al., 2021, China | Both | Exosomal miRNA content has the potential to be used as a diagnostic and therapeutic tool in neurodegenerative disease. | He et al., 2021 |
| 27 | Kapogiannis, 2020, USA | Both | EV-based biomarkers are a valuable new tool that will allow researchers to test hypotheses in preclinical proof-of-concept studies with carefully selected participants, propelling therapeutic discovery in neurodegenerative disease. | Kapogiannis, 2020 |
| 28 | Thompson et al., 2016, UK | Diagnostic | The trafficking of macromolecules from the CNS to the cerebrospinal fluid and blood via extracellular vesicles (EVs) represents a promising source of CNS-specific biomarkers, and thus EVs could provide an enriched pool of information about core neuropathogenic, cell-specific processes. | Thompson et al., 2016 |
| 29 | Vella et al., 2016, Australia | Diagnostic | Exosomes contain proteins associated with neurodegenerative diseases such as prion protein, -amyloid, and -synuclein. Alzheimer’s and Parkinson’s disease, including their possible role in disease propagation and pathology, as well as their utility as a diagnostic in neurodegenerative disease. |
Vella et al., 2016 |
| 30 | Lee et al., 2019, South Korea | Diagnostic | Extracellular vesicles (EVs), which are released by almost all cell types, act as a mediator in the regulation of AD pathogenesis. EV biochemical AD biomarkers, such as proteins and miRNAs. EVs will aid in the early detection of Alzheimer’s disease and the identification of new therapeutic targets. |
Lee et al., 2019 |
| 31 | Vinaiphat and Sze, 2019, Singapore | Diagnostic | EVs and understanding their mechanism of action could pave the way for the discovery of disease-specific biomarkers and therapeutic targets in neurodegenerative disease. | Vinaiphat and Sze, 2019 |
| 32 | Pulliam et al., 2019, USA | Diagnostic | EVs derived from neural cells have the potential to be exciting biomarkers of neurodegeneration in Alzheimer’s disease. | Pulliam et al., 2019 |
| 33 | Ramirez et al., 2018, USA | Diagnostic | EVs released from all circulating blood elements, as well as the luminal surface of the endothelium, can be used as biomarkers in CSF. | Ramirez et al., 2018 |
| 34 | Banack et al., 2020, USA | Diagnostics | Neural-enriched extracellular vesicles may provide microRNA (miRNA) fingerprints with unequivocal neurodegeneration signs that can be used as a biomarker. | Banack et al., 2020 |
| 35 | Barreca et al., 2017, Italy | Diagnostics | Because EVs are involved in the pathogenesis of multiple sclerosis, they could be used as a biomarker. | Barreca et al., 2017 |
| 36 | Guedes et al., 2020, USA | Diagnostic | Exosomes, which can cross the blood-brain barrier and be isolated from peripheral fluids such as serum, saliva, sweat, and urine, are promising TBI biomarkers. | Guedes et al., 2020 |
| 37 | Gámez-Valero et al., 2019, Spain | Diagnostic | Specific biomarkers will aid in the resolution of overlapping features of various dementias. Extracellular vesicles (EVs) are a dependable and stable biomarker source that can be found in a variety of bodily fluids. EV proteins and miRNAs may define the pathology’s specific biosignature. |
Gámez-Valero et al., 2019 |
| 38 | Karnati et al., 2019, Maryland | Diagnostic | EVs enriched for neuronal origin can be extracted from peripheral blood samples and their contents quantified as a window into potential brain changes. Exosomal proteins and microRNAs (miRNAs) may be novel biomarkers to aid in the clinical diagnosis and treatment response of neurological disorders. |
Karnati et al., 2019 |
| 39 | Pluta et al., 2018, Poland | Diagnostic | Exosomes secreted in Alzheimer’s disease may aid in spreading and progression, highlighting their potential utility as future diagnostic antemortem biomarkers in this devastating disease. | Pluta et al., 2018 |
| 40 | Hornung et al., 2020, USA | Diagnostic | CNS-derived exosomes have also been shown to cross the blood-brain barrier into the bloodstream, attracting significant interest as a source of biomarkers for various neurodegenerative diseases because they can be isolated using a minimally invasive blood draw. | Hornung et al., 2020 |
| 41 | Li et al., 2018, China | Diagnostic | Amyloid -protein, -synuclein, Huntington-associated protein 1, and superoxide dismutase I can be transported to other cells by exosomes in the CNS. The network of exosomes that regulates CNS homeostasis is a promising biomarker for neurodegenerative disease diagnosis and treatment. |
Li et al., 2018 |
| 42 | Coleman and Hill, 2015, Australia | Diagnostic | Exosomes also play a role in the processing of the amyloid precursor protein (APP), which is linked to Alzheimer’s disease (AD). Exosomes are a potential source of biomarkers for neurological conditions because they can be isolated from circulating fluids such as serum, urine, and cerebrospinal fluid (CSF). | Coleman and Hill, 2015 |
| 43 | Leggio et al., 2021, Italy | Diagnostic | Parkinson’s disease patient-derived EVs derived from a variety of biological specimens can be investigated as diagnostic biomarkers. | Leggio et al., 2021 |
| 44 | Pluta and Ułamek-Kozioł, 2019, Poland | Diagnostic | EVs can be used as biomarker in AD. | Pluta and Ułamek-Kozioł, 2019 |
| 45 | Rani et al., 2020, India | Diagnostic | Exosomes can be utilized in the diagnosis of neurodegenerative disorders due to their easy availability from most biological fluids such as blood, urine, saliva, breast milk, sperm, and so on, their extremely high disease-specific bio-molecular signature/profile, exosomes’ ability to cargo a variety of biomolecules in between cells, and their ability to cross the blood-brain barrier. | Rani et al., 2020 |
| 46 | Chen et al., 2017, China | Diagnostic | Exosomal miRNAs in Alzheimer’s disease pathology exploits the potential of these miRNAs as diagnostic biomarkers in Alzheimer’s disease, as well as the use of exosomes in miRNA delivery, which may lead to significant advances in the field of macromolecular drug delivery. | Chen et al., 2017 |
| 47 | Rufino-Ramos et al., 2017, Portugal | Therapeutics | EVs linked to AAV vectors (vexosomes), enveloped protein nanocages (EPNs), and exosome-mimetic nanovesicles can be used as therapeutic vehicles. | Rufino-Ramos et al., 2017 |
| 48 | Lakshmi et al., 2020, India | Therapeutics | The ability of exosomes to increase A clearance suggests a novel therapeutic role for exosomes in Alzheimer’s disease intervention. | Lakshmi et al., 2020 |
| 49 | Kumar et al., 2021, USA | Therapeutics | Because of their biocompatibility, stability, and targeted delivery with limited immunogenicity, as well as their ability to be delivered via a non-invasive approach for the treatment of neurodegenerative diseases, EVs can be used as a drug delivery system. | Kumar et al., 2021 |
| 50 | Dolcetti et al., 2020, Italy | Therapeutics | EVs as potential therapeutic targets and tools for therapeutic intervention in multiple sclerosis. | Dolcetti et al., 2020 |
| 51 | Upadhya et al., 2020, USA | Therapeutics | Naive astrocytes release EVs containing a variety of neuroprotective compounds such as fibroblast growth factor-2, vascular endothelial growth factor, and apolipoprotein-D. When astrocytes are stimulated, they secrete EVs containing neuroprotective molecules such as heat shock proteins, synapsin 1, unique microRNAs, and glutamate transporters. Astrocyte-derived EVs (ADEVs) derived from specific culture conditions, as well as ADEVs engineered to carry desired miRNAs or proteins, are likely to be useful in treating brain injury and neurodegenerative disease. |
Upadhya et al., 2020 |
| 52 | Sarko and McKinney, 2017, USA | Therapeutics | Exosomal content has been shown to aid in the promotion of neurodegeneration pathways such as -amyloid peptide (A) accumulation forming amyloid plaques in Alzheimer’s disease brains and pathological aggregates of proteins containing -synuclein in Parkinson’s disease transferred to the central nervous system via exosomes. Exosomes can cross the blood-brain barrier, can be strategically engineered to carry drugs or other treatments, and have an appropriate half-life and stability for this purpose. |
Sarko and McKinney, 2017 |
| 53 | Araldi et al., 2020, Brazil | Therapeutics | Stem cell-derived exosomes can be used as therapeutic approach for Neurodegenerative Disorders. | Araldi et al., 2020 |
| 54 | Xu et al., 2021, China | Therapeutics | Bioengineered EVs can have the ability to cross BBB and can be effectively used for therapeutic purposes. | Xu et al., 2021 |
| 55 | Meldolesi, 2022, Italy | Therapeutics | Stem cells contains blockers of the enzyme BACE-1, that induce, in neurons and glial cells and decreased levels of Aβ, the key peptide of the Alzheimer’s disease and a resultant showed therapeutic effect. | Meldolesi, 2022 |
| 56 | Fayazi et al., 2021, Iran | Therapeutics | Stem cell-derived exosomes can be explored in treatment of various neurodegenerative diseases. | Fayazi et al., 2021 |
| 57 | Haney et al., 2021, USA | Therapeutics | EVs secreted from macrophages are suggested as the most promising nanocarrier system for drug delivery to the brain | Haney et al., 2021 |
| 58 | Reed and Escayg, 2021, Georgia | Therapeutics | EVs attenuate reactive gliosis, neuronal death, pro-inflammatory signaling, as well as reduce cognitive, behavioral, and motor deficits. EVs can be used as therapeutics in neurodegenerative diseases |
Reed and Escayg, 2021 |
| 59 | Kim et al., 2013, South Korea | Therapeutics | MSCs secrete trophic factors and cytokines (secretome) that have therapeutic relevance for the neurogenic, neuroprotective, angiogenic and anti-inflammatory/immunoregulatory activities. MSCs secreted exosomes have therapeutic role in neurodegenerative disease. |
Kim et al., 2013 |
| 60 | Katsuda et al., 2015, Japan | Therapeutics | EVs secreted from human adipose tissue-derived MSCs (hADSCs) (also known as adipose tissue-derived stem cells; ASCs) against Alzheimer’s disease (AD). hADSCs secrete exosomes carrying enzymatically active neprilysin, the most important β-amyloid peptide (Aβ)-degrading enzyme in the brain |
Katsuda et al., 2015 |