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Cited by 229Extracellular vesicles in diseaseNanoparticle-Based Drug DeliveryRNA Interference and Gene Delivery

Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies

Open access
Xu, Meng, Feng, Tao, Liu, Bowen, Qiu, Fen, Xu, Youhua, Zhao, Yonghua, Zheng, Ying·2021·Theranostics
DOI 10.7150/thno.62330PMC PMC8419041
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Abstract

As extracellular vesicles secreted by cells, exosomes are intercellular signalosomes for cell communication and pharmacological effectors. Because of their special properties, including low toxicity and immunogenicity, biodegradability, ability to encapsulate endogenous biologically active molecules and cross the blood-brain barrier (BBB), exosomes have great therapeutic potential in cerebrovascular and neurodegenerative diseases. However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect. Using engineering technology, exosomes can obtain active targeting ability to accumulate in specific cell types and tissues by attaching targeting units to the membrane surface or loading them into cavities. In this review, we outline the improved targeting functions of bioengineered exosomes, tracing and imaging techniques, administration methods, internalization in the BBB, and therapeutic effects of exosomes in cerebrovascular and neurodegenerative diseases and further evaluate the clinical opportunities and challenges in this research field.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how engineered exosomes can acquire active brain-targeting ability for cerebrovascular and neurodegenerative disease therapy, covering administration routes, blood-brain barrier (BBB) crossing/regulation, engineering strategies, therapeutic effects, and tracking/imaging. It argues that engineering can improve targeting and reduce off-target damage, but clinical translation remains limited by unresolved isolation, standardization, dosing, safety, and quality-control issues.

Key findings

  • Exosomes can cross the BBB and be internalized by brain endothelial cells via endocytosis/transcellular routes; they can also regulate BBB integrity, e.g., neuron-derived miR-132 exosomes target eef2k and regulate vascular endothelial cadherin, while breast cancer exosomal miR-105 targets ZO-1 and reduces BBB integrity.
  • Engineering strategies include genetic engineering (e.g., RVG-Lamp2b exosomes knocked down BACE1 mRNA and protein up to 60% in wild-type mice), biochemical modification (e.g., cRGD-Exo increased ipsilateral/contralateral fluorescence ratio to 11 in mouse MCAO/R), and physical engineering (e.g., magnetic nanovesicles accumulated 5.1 times more in ischemic lesions, with left/right hemisphere fluorescence ratio 9.2).
  • Administration routes reviewed are intravenous, oral, stereotactic, and nasal; nasal administration bypassed the BBB and MSC-exos stayed in brain up to 96 h by CT tracking, while oral ExoCUR increased curcumin drug content 3–5 times versus free curcumin.
  • Tracking methods include fluorescence, bioluminescence, radionuclide, and MRI; B16-BL6 exosomes had a blood half-life of approximately 2 min by bioluminescence, and 125I-labeled B16BL6 exosomes showed about 1.6%, 7%, and 28% of injected radiation in spleen, lung, and liver at 4 h.

Methods

  • Design: narrative review of engineered exosomes for cerebrovascular and neurodegenerative disease therapies, including administration routes, BBB interactions, engineering strategies, therapeutic applications, and imaging/tracking techniques.
  • Data: synthesis of published preclinical and clinical literature, with summary tables of brain-targeted engineered exosomes and exosome tracking techniques; no primary experiments or systematic meta-analysis are reported.
  • Main analysis: qualitative synthesis of cited studies, including reported targeting efficiencies, biodistribution, therapeutic effects, and translational challenges.

Limitations

  • The paper states that there is still no definite optimal purification technique for high-purity exosome isolation; existing separation, quantification, and characterization methods differ, making studies hard to compare.
  • The paper states unresolved issues in dosage, measurement standards, administration routes, possible adverse effects with therapeutic cargos, heterogeneity-related immunogenicity, source-cell physiological state effects, and the need for quality-control standards and fuller understanding of in vivo trafficking and biological fate.
  • Evident from the text: as a narrative review, it does not provide a systematic search strategy, risk-of-bias assessment, or quantitative pooled analysis, and much of the cited evidence comes from animal models rather than clinical trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.7150/thno.62330

Cites

154 of 154 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 114 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The blood circulation of exosomes is easily cleared by macrophages.

    “In addition, the blood circulation of exosomes is easily cleared by macrophages 52, 53.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Liu X Yang Y Li Y Niu X Zhao B Wang Y Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration Nanoscale 2017 9 4430 38 28300264

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    • cites [53] Takahashi Y Nishikawa M Takakura Y Analysis and control of in vivo kinetics of exosomes for the development of exosome-based dds Yakugaku Zasshi 2016 136 49 53 26725667

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  • Premisecitation

    In a mouse Parkinson's disease model, exosomes containing catalase delivered by intravenous injection protect SNpc neurons from acute oxidative stress.

    “In a mouse Parkinson's disease model, exosomes containing catalase were successfully delivered to the brain by intravenous injection to protect SNpc neurons in mice with brain inflammation from acute oxidative stress 40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation

    Intravenous injection of MSC-derived exosomes reduced infarct area by approximately 50% in a mouse model of myocardial ischemia-reperfusion injury.

    “In early 2010, Lai RC et al. protected the heart function of mice by intravenous injection of exosomes, which significantly reduced the infarct area of MIR injury in the mouse model by approximately 50%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Lai RC Arslan F Lee MM Sze NS Choo A Chen TS Exosome secreted by msc reduces myocardial ischemia/reperfusion injury Stem Cell Res 2010 4 214 22 20138817

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  • Premisecitation

    The specificity of exosomes gives them different half-lives and distributions in vivo.

    “The specificity of exosomes makes them have different half-lives and distributions in vivo 23, 24, which confirms the vital role of exosome biomarkers in tracking exosome fate.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Yuan D Zhao Y Banks WA Bullock KM Haney M Batrakova E Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain Biomaterials 2017 142 1 12 28715655 PMC5603188

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    • cites [24] Morishita M Takahashi Y Nishikawa M Sano K Kato K Yamashita T Quantitative analysis of tissue distribution of the b16bl6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice J Pharm Sci 2015 104 705 13 25393546

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  • Premisecitation

    miRNA-150-carrying exosomes from suppressor T cells and B1a cells effectively induce long-term inhibition of delayed-type hypersensitivity after a single systemic administration in mice.

    “Nazimek K et al. found that miRNA-150-carrying exosomes from suppressor T cells and B1a cells could effectively induce long-term inhibition of delayed-type hypersensitivity (DTH) after a single systemic administration in mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Nazimek K Bryniarski K Ptak W Groot Kormelink T Askenase PW Orally administered exosomes suppress mouse delayed-type hypersensitivity by delivering mirna-150 to antigen-primed macrophage apc targeted by exosome-surface anti-peptide antibody light chains Int J Mol Sci 2020 21 5540 73 PMC7432818 32748889

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  • May combine two claims. 66
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    Natural exosomes have poor targeting ability, which greatly reduces their therapeutic effect.

    “However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect.”
    • Also stated in: § Introduction · boosted
      “Although the homing function of exosomes has great potential in treatment, it has been verified that their targeting ability is inefficient in animal experiments 21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Tian T Zhang HX He CP Fan S Zhu YL Qi C Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy Biomaterials 2018 150 137 49 29040874

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Systemic administration of mesenchymal stem cell-derived exosomes after stroke improves functional recovery and enhances angiogenesis, neurite remodeling and neurogenesis.

    “A previous study indicated that systemic administration of mesenchymal stem cell-derived exosomes (MSC-Exos) post stroke could improve functional recovery and enhance angiogenesis, neurite remodeling and neurogenesis 19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Xin H Li Y Cui Y Yang JJ Zhang ZG Chopp M Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neur ovascular plasticity after stroke in rats J Cereb Blood Flow Metab 2013 33 1711 15 23963371 PMC3824189

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    Premisecitation

    Exosomes for oral drug delivery can solve drug solubility and reduce therapeutic indicators and toxicity compared to free drugs.

    “In addition, exosomes for oral drug delivery systems can solve the following problems: 1) the solubility of drugs and 2) the reduction of therapeutic indicators and toxicity compared to free drugs 54, 55.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Barile L Vassalli G Exosomes: Therapy delivery tools and biomarkers of diseases Pharmacol Ther 2017 174 63 78 28202367

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    • cites [55] Mittal G Carswell H Brett R Currie S Kumar MNVR Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of alzheimer's pathology J Control Release 2011 150 220 28 21111014

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    Premisecitation

    Intravenous injection of MSCs-Ex intensifies PI3K/Akt/mTOR/GSK-3β signaling by targeting PTEN, increasing nerve differentiation and plasticity, and improving nerve function after stroke.

    “Xin H et al. found that intravenous injection of MSCs-Ex could intensify the PI3K/Akt/mTOR/GSK-3β signaling pathway by targeting PTEN, increasing nerve differentiation and plasticity, and improving nerve function after stroke 50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Xin H Katakowski M Wang F Qian JY Liu XS Ali MM Microrna cluster mir-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats Stroke 2017 48 747 53 28232590 PMC5330787

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    Premisecitation

    Intravenously injected exosomes can be tracked in the brain and significantly improve learning and memory, reduce plaque deposition and Aβ levels, and normalize inflammatory cytokine levels.

    “Cui GH et al. found that intravenously injected exosomes could be tracked in the brain and proved to significantly improve learning and memory abilities, reduce plaque deposition and Aβ levels, and normalize inflammatory cytokine levels 51.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Cui GH Guo HD Li H Zhai Y Gong ZB Wu J Rvg-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of alzheimer's disease Immun Ageing 2019 16 10 21 31114624 PMC6515654

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MSC-Exos reduce inflammation and prevent abnormal neurogenesis by acting on astrocytes, showing potential in stroke, temporal lobe epilepsy, Alzheimer's disease, and Parkinson's disease.

    “Another study proposed that MSC-Exos reduced inflammation and prevented abnormal neurogenesis by acting on astrocytes, showing great potential in the treatment of neurological diseases, such as stroke, temporal lobe epilepsy, Alzheimer's disease, and Parkinson's disease 20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Xian P Hei Y Wang R Wang T Yang J Li J Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice Theranostics 2019 9 5956 75 31534531 PMC6735367

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    Premisecitation

    The exosome membrane structure can be easily labeled and exosome markers are tightly connected, so changes in biomarkers can be monitored when a patient receives effective treatment.

    “Since the membrane structure of exosomes can be easily labeled and exosome markers are tightly connected, changes in biomarkers can be monitored when the patient receives effective treatment 22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Mirzaei H Momeni F Saadatpour L Sahebkar A Goodarzi M Masoudifar A Microrna: Relevance to stroke diagnosis, prognosis, and therapy J Cell Physiol 2018 233 856 65 28067403

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    Premisecitation

    In mice immunized with OVA DTH, OVA-specific suppressor T cell-derived exosomes significantly inhibit DTH ear swelling via intravenous, intraperitoneal, intradermal and oral administration, with the strongest effect after oral treatment.

    “All of these administration routes could significantly inhibit DTH ear swelling, and the strongest effect was observed after oral treatment 56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Nazimek K Bryniarski K Ptak W Groot Kormelink T Askenase PW Orally administered exosomes suppress mouse delayed-type hypersensitivity by delivering mirna-150 to antigen-primed macrophage apc targeted by exosome-surface anti-peptide antibody light chains Int J Mol Sci 2020 21 5540 73 PMC7432818 32748889

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intravenous injection of exosome-mediated miR-210 upregulates VEGF and CD34, indicating improved angiogenesis and significantly increased animal survival.

    “Zhang H et al. achieved targeted delivery of exosome-mediated miR-210 by intravenous injection. The results of upregulation of VEGF and CD34 indicate improved angiogenesis and a significant increase in animal survival 31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Zhang H Wu J Wu J Fan Q Zhou J Wu J Exosome-mediated targeted delivery of mir-210 for angiogenic therapy after cerebral ischemia in mice J Nanobiotechnology 2019 17 29 30782171 PMC6379944

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    Premisecitation

    Intravenous injection is the most widely used route for exosome administration.

    “Intravenous injection is the most widely used route for exosome administration 48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Akbari A Jabbari N Sharifi R Ahmadi M Vahhabi A Seyedzadeh SJ Free and hydrogel encapsulated exosome-based therapies in regenerative medicine Life Sci 2020 249 117447 58 32087234

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    Premisecitation

    Stereotactic brain injection is the most direct and accurate route to transport exosomes to the target structure but faces difficulties including high equipment and operative skill requirements, need for imaging guidance, risk of brain damage from injection deviation, and complications from anesthesia and surgery.

    “Although stereotactic brain injection is the most direct and accurate route to transport exosomes to the target structure, it still faces many difficulties. Stereotactic injection has high requirements for equipments and operative skills, and imaging guidance is also needed to locate the target position. Injection deviation may cause serious brain damage. Moreover, anesthesia and surgical procedu”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Kim HJ Seo SW Chang JW Lee JI Kim CH Chin J Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with alzheimer's disease dementia: A phase 1 clinical trial Alzheimers Dement (N Y) 2015 1 95 102 29854930 PMC5975048

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    Premisecitation

    The effects of microorganisms and enzyme digestion in gastrointestinal fluid on the structural integrity of exosomes need to be considered.

    “In addition, the effects of microorganisms and enzyme digestion in gastrointestinal fluid on the structural integrity of exosomes also need to be considered 58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Agrawal AK Aqil F Jeyabalan J Spencer WA Beck J Gachuki BW Milk-derived exosomes for oral delivery of paclitaxel Nanomedicine 2017 13 1627 36 28300659

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    Premisecitation

    Stereotaxic injection of ECs-exo into the ventricle of rat brain achieves better accumulation around the lesion and exerts long-term effects.

    “On this basis, they stereotaxically injected ECs-exo into the ventricle of rat's brain to achieve better accumulate around the lesion, thereby exerting long-term effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Gao B Zhou S Sun C Cheng D Zhang Y Li X Brain endothelial cell-derived exosomes induce neuroplasticity in rats with ischemia/reperfusion injury ACS Chem Neurosci 2020 11 2201 13 32574032

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    Premisecitation

    ECs-exo containing microRNA-126-3p upregulate plasticity signal genes, change neural plasticity of motor cortex, and positively regulate synaptic plasticity during stroke recovery.

    “ECs-exo containing microRNA-126-3p upregulated gene expression related to plasticity signal, changed neural plasticity of motor cortex, and positively regulated synaptic plasticity during stroke recovery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Gao B Zhou S Sun C Cheng D Zhang Y Li X Brain endothelial cell-derived exosomes induce neuroplasticity in rats with ischemia/reperfusion injury ACS Chem Neurosci 2020 11 2201 13 32574032

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    Premisecitation

    Intraventricular injection of ECs-exo promotes functional motor recovery in the MCAO/R model and plays a crucial role in synaptic function reconstruction in ischemic brain injury.

    “This study suggested that ECs-exo intraventricular injection promoted functional motor recovery in the middle cerebral artery occlusion (MCAO)/R model and played a crucial role in synaptic function reconstruction in ischemic brain injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Gao B Zhou S Sun C Cheng D Zhang Y Li X Brain endothelial cell-derived exosomes induce neuroplasticity in rats with ischemia/reperfusion injury ACS Chem Neurosci 2020 11 2201 13 32574032

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    Premisecitation

    Stereotactic injection solves problems of poor stability, off-target toxicity, and poor drug release repeatability and reduces retention time, dose, toxicity and side effects.

    “Stereotactic injection not only solves the problems of poor stability, off-target toxicity, and poor drug release repeatability but also reduces the retention time, the dose, and the toxicity and side effects of the drug 62.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Neffendorf JE Jackson TL Stereotactic radiotherapy for wet age-related macular degeneration: Current perspectives Clin Ophthalmol 2015 9 1829 34 26491243 PMC4599143

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    Premisecitation

    Exosomes isolated from bEnd.3 cells by ultracentrifugation attenuate infarct volume, activate proliferation and migration of neural progenitor cells, and promote neurogenesis in periinfarct area, SVZ and DG area of hippocampus.

    “Zhou ST et al. demonstrated that exosomes isolated from bEnd.3 cells by ultracentrifugation could attenuate infarct volume, activate the proliferation and migration of neural progenitor cells, and promote neurogenesis in periinfarct area, subregion of subventricular zone (SVZ) and dentate gyrus (DG) area of hippocampus 43.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Zhou ST Gao BY Sun CC Bai YL Cheng DD Zhang Y Vascular endothelial cell-derived exosomes protect neural stem cells against ischemia/reperfusion injury Neuroscience 2020 441 184 96 32502570

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    Premisecitation

    Nasal exosome administration is noninvasive, suitable for repeated distribution, and leads to rapid penetration of exosomes into multiple areas of the forebrain.

    “Nasal exosome administration has attracted widespread attention because this process is noninvasive, suitable for repeated distribution, and leads to rapid penetration of exosomes into multiple areas of the forebrain 71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Kodali M Castro OW Kim DK Thomas A Shuai B Attaluri S Intranasally administered human msc-derived extracellular vesicles pervasively incorporate into neurons and microglia in both intact and status epilepticus injured forebrain Int J Mol Sci 2019 21 181 95 PMC6981466 31888012

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    Premisecitation

    The two main routes of intranasal drug absorption are the olfactory and trigeminal nerve pathways, which bypass the BBB and blood-cerebrospinal fluid barrier, and transporter regulation can help nasal delivery of its substrate.

    “The two main routes of intranasal drug absorption are the olfactory and trigeminal nerve pathways, which can bypass the BBB and the blood-cerebrospinal fluid barrier, and transporter regulation can also help nasal delivery of its substrate 68, 69.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Kou L Yao Q Sivaprakasam S Luo Q Sun Y Fu Q Dual targeting of l-carnitine-conjugated nanoparticles to octn2 and atb(0,+) to deliver chemotherapeutic agents for colon cancer therapy Drug Deliv 2017 24 1338 49 28911246 PMC8241000

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    • cites [69] Kou L Bhutia YD Yao Q He Z Sun J Ganapathy V Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types Front Pharmacol 2018 9 27 42 29434548 PMC5791163

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    Premisecitation

    Nasal administration of MSC-derived A1 exosomes reduces inflammation and prevents memory dysfunction or abnormal neurogenesis after status epilepticus.

    “Long Q et al. found that administering MSC-derived A1 exosomes through the nasal cavity could reduce inflammation and prevent memory dysfunction or abnormal neurogenesis after status epilepticus 73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Long Q Upadhya D Hattiangady B Kim DK An SY Shuai B Intranasal msc-derived a1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus Proc Natl Acad Sci U S A 2017 114 3536 45 PMC5410779 28396435

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    Premisecitation

    In zebrafish embryos, rhodamine 123 delivered by brain endothelial bEND.3 cell-derived exosomes shows significant penetration in brain regions, whereas free rhodamine 123 remains within blood vessels and is not observed in brain tissue.

    “When given alone, rhodamine 123 remained within the blood vessels and was not observed in the brain tissue. In contrast, when delivered by brain endothelial bEND.3 cells-derived exosomes, rhodamine 123 showed significant penetration in brain regions, confirming the ability of exosomes to deliver drugs across BBB for brain diseases treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Yang T Martin P Fogarty B Brown A Schurman K Phipps R Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in danio rerio Pharm Res 2015 32 2003 14 25609010 PMC4520542

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    Premisecitation

    Intranasal administration has disadvantages including relatively small dosage, limited surface area of olfactory epithelium, short retention time of drug absorption, and effects on nasal secretions.

    “However, intramural administration also has some disadvantages, including relatively small dosage, limited surface area of olfactory epithelium, short retention time of drug absorption and its effect on nasal secretions 67, 75.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Erdő F Bors LA Farkas D Bajza Á Gizurarson S Evaluation of intranasal delivery route of drug administration for brain targeting Brain Res Bull 2018 143 155 70 30449731

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    • cites [75] Wu H Hu K Jiang X From nose to brain: Understanding transport capacity and transport rate of drugs Expert Opin Drug Deliv 2008 5 1159 68 18817519

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    Premisecitation

    Cerebral microvascular endothelial cells connect with each other through junction proteins, and tight junctions between endothelial cells block the paracellular pathway.

    “ECs connect with each other through junction proteins, and the tight junctions (TJs) between endothelial cells block the paracellular pathway.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] De Bock M Van Haver V Vandenbroucke R Decrock E Wang N Leybaert L Into rather unexplored terrain-transcellular transport across the blood-brain barrier Glia 2016 64 1097 123 26852907

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    • cites [84] Saint-Pol J Gosselet F Duban-Deweer S Pottiez G Karamanos Y Targeting and crossing the blood-brain barrier with extracellular vesicles Cells 2020 9 851 63 PMC7226770 32244730

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  • May combine two claims.

    Premisecitation

    Most exosomes cross BMEC monolayers via a transcellular pathway, while only a small number pass through the paracellular route.

    “In addition, most exosomes crossed the BMEC monolayers via a transcellular pathway (i.e., endocytosis on the other side of the translayer, MVB formation and exocytosis) while only a small number of exosomes pass through the paracellular route (i.e., passive diffusion though intercellular space between BMECs).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Chen CC Liu L Ma F Wong CW Guo XE Chacko JV Elucidation of exosome migration across the blood-brain barrier model in vitro Cell Mol Bioeng 2016 9 509 29 28392840 PMC5382965

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  • May combine two claims.

    Premisecitation

    Exosomes derived from breast cancer cells specifically express miR-105, which directly targets the TJ protein ZO-1 and reduces the integrity of the BBB.

    “Zhou W et al. found that exosomes derived from breast cancer cells could specifically express miR-105, which could directly target the TJ protein ZO-1 (a central molecular component of TJs) and reduce the integrity of the BBB 89.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Zhou W Fong MY Min Y Somlo G Liu L Palomares MR Cancer-secreted mir-105 destroys vascular endothelial barriers to promote metastasis Cancer Cell 2014 25 501 15 24735924 PMC4016197

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  • May combine two claims.

    Interpretationreasoning

    The uptake of exosomes in BMECs may depend on specific lipid rafts or ligand receptors, and the mechanism varies with different cell sources.

    “Generally, the uptake of exosomes in BMECs may depend on specific lipid rafts or ligand receptors, and the mechanism of uptake of exosomes varies with different cell sources.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Exosomes secreted by different cells may have different cargo, including proteins and lipids, which may change the way they cross the BBB.

    “Exosomes secreted by different cells may have different cargo, including proteins and lipids, which may change the way they cross BBB 87, 88.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Montecalvo A Larregina AT Shufesky WJ Stolz DB Sullivan ML Karlsson JM Mechanism of transfer of functional micrornas between mouse dendritic cells via exosomes Blood 2012 119 756 66 22031862 PMC3265200

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    • cites [88] Hu GW Li Q Niu X Hu B Liu J Zhou SM Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice Stem Cell Res Ther 2015 6 10 24 26268554 PMC4533800

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    Premiseown data

    Mφ-EXO inherited LFA-1 from parental cells, which interacts with endothelial ICAM-1 and mediates lateral migration of Mφ-EXO on the BBB.

    “The authors further verified that Mϕ-EXO inherited LFA-1 from their parental cells. This protein interacted with endothelial ICAM-1 and mediated the lateral migration of Mϕ-EXO on BBB.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Yuan D Zhao Y Banks WA Bullock KM Haney M Batrakova E Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain Biomaterials 2017 142 1 12 28715655 PMC5603188

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exosomes secreted by human dental pulp stem cells increase vascular permeability in the initial stage of acute inflammation and then suppress carrageenan-induced acute inflammation in mice.

    “Pivoraitė U et al. demonstrated for the first time that exosomes secreted by human dental pulp stem cells (DPSCs) could increase vascular permeability in the initial stage of acute inflammation and then suppress carrageenan-induced acute inflammation in mice model 90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Pivoraitė U Jarmalavičiūtė A Tunaitis V Ramanauskaitė G Vaitkuvienė A Kašėta V Exosomes from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice Inflammation 2015 38 1933 41 25903966

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  • May combine two claims.

    Premisecitation

    Luciferase-carrying exosomes are internalized by BMECs and more effectively cross the BMEC monolayer under stroke-like conditions.

    “The results showed that luciferase-carrying exosomes (hGluc-Lact exosomes) could be internalized by BMECs and more effectively crossed the BMEC monolayer under stroke-like conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Chen CC Liu L Ma F Wong CW Guo XE Chacko JV Elucidation of exosome migration across the blood-brain barrier model in vitro Cell Mol Bioeng 2016 9 509 29 28392840 PMC5382965

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  • May combine two claims.

    Interpretationreasoning

    The disease state may affect the methods of BBB crossing, as the cargo may change with the disease state.

    “In addition, the disease state may also affect the methods of BBB crossing, as the cargo may change with the disease state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exosomes are internalized by BMECs through endocytosis and accumulate in endosomes.

    “Exosomes were internalized by BMECs through endocytosis and accumulated in endosomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Chen CC Liu L Ma F Wong CW Guo XE Chacko JV Elucidation of exosome migration across the blood-brain barrier model in vitro Cell Mol Bioeng 2016 9 509 29 28392840 PMC5382965

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    Premisecitation

    The barrier function of endothelial cells comes from a metabolic barrier supported by enzymes and efflux pumps and a physical barrier through apical tight junctions.

    “The barrier function of ECs mainly comes from the following two components: 1) the metabolic barrier supported by enzymes and efflux pumps (e.g., P-glycoprotein and multidrug-resistance proteins (MRPs)) that limits nonspecific transport and facilitates receptor- or transporter-specific pathways and 2) the physical barrier that limits the intercellular action of cells through apical TJs and closes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Saint-Pol J Gosselet F Duban-Deweer S Pottiez G Karamanos Y Targeting and crossing the blood-brain barrier with extracellular vesicles Cells 2020 9 851 63 PMC7226770 32244730

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exosomes have characteristics that promote ideal delivery of biopharmaceuticals, including ability to cross biological membranes or barriers, low immunogenicity, noncytotoxicity, and good circulation stability.

    “The characteristics of exosomes that promote the ideal delivery of biopharmaceuticals include their ability to cross biological membranes or barriers to efficiently transfer their payloads to recipient cells, as well as their low immunogenicity, noncytotoxicity, and good circulation stability 24, 96.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Morishita M Takahashi Y Nishikawa M Sano K Kato K Yamashita T Quantitative analysis of tissue distribution of the b16bl6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice J Pharm Sci 2015 104 705 13 25393546

      Not checked in the free run.

    • cites [96] Smyth T Kullberg M Malik N Smith-Jones P Graner MW Anchordoquy TJ Biodistribution and delivery efficiency of unmodified tumor-derived exosomes J Control Release 2015 199 145 55 25523519 PMC4441346

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The complex pathogenesis of brain diseases and the lack of effective and specific recognition epitopes greatly hinder the clinical application of exosomes.

    “Due to the complex pathogenesis of brain diseases, the lack of effective and specific recognition epitopes greatly hinders the clinical application of exosomes 97, 98.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [97] de Abreu RC Fernandes H da Costa Martins PA Sahoo S Emanueli C Ferreira L Native and bioengineered extracellular vesicles for cardiovascular therapeutics Nat Rev Cardiol 2020 17 685 97 32483304 PMC7874903

      Not checked in the free run.

    • cites [98] Mustapic M Tran J Craft S Kapogiannis D Extracellular vesicle biomarkers track cognitive changes following intranasal insulin in alzheimer's disease J Alzheimers Dis 2019 69 489 98 30958348 PMC6668911

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After intravenous administration, ECFC-derived exosome treatment reduces BBB permeability and improves recovery of neurological function post-injury.

    “After intravenous administration, exosome treatment reduced the permeability of BBB and improved the recovery of neurological function post-injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Gao WW Li F Liu L Xu X Zhang BL Wu YG Endothelial colony-forming cell-derived exosomes restore blood-brain barrier continuity in mice subjected to traumatic brain injury Exp Neurol 2018 307 99 108 29883579

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Complete transmembrane proteins CD81 and CD9 and integrins CD51 and CD61 in exosomes have certain homing and targeting functions, but their targeting ability is too weak to be applied.

    “Although the complete transmembrane proteins (CD81 and CD9) and integrins (CD51 and CD61) in exosomes are considered to have certain homing and targeting functions, their targeting ability is still too weak to be applied 99.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Fitzner D Schnaars M van Rossum D Krishnamoorthy G Dibaj P Bakhti M Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis J Cell Sci 2011 124 447 58 21242314

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The surface protein composition of exosomes is significantly different from that of the plasma membrane, as Class II MHCs bound by exosomes are in a tight peptide-bound conformation.

    “Raposo G et al. found that the surface protein composition of exosomes was significantly different from that of the plasma membrane, as Class II MHCs bound by exosomes were in a tight peptide-bound conformation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [101] Raposo G Nijman HW Stoorvogel W Liejendekker R Harding CV Melief CJ B lymphocytes secrete antigen-presenting vesicles J Exp Med 1996 183 1161 72 8642258 PMC2192324

      Not checked in the free run.

    • cites [102] Zitvogel L Regnault A Lozier A Wolfers J Flament C Tenza D Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes Nat Med 1998 4 594 600 9585234

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ECFC-derived exosomes are highly absorbed by endothelial cells, promote EC migration, inhibit PTEN expression, and increase AKT phosphorylation and TJ protein expression in hypoxia-exposed ECs.

    “These exosomes were highly absorbed by ECs, subsequently promoted the migration of ECs, inhibited PTEN expression, and increased AKT phosphorylation and TJ protein expression in hypoxia-exposed ECs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Gao WW Li F Liu L Xu X Zhang BL Wu YG Endothelial colony-forming cell-derived exosomes restore blood-brain barrier continuity in mice subjected to traumatic brain injury Exp Neurol 2018 307 99 108 29883579

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Exosomes secreted by different cell sources can affect vascular permeability and in some cases affect the integrity of the BBB, thus playing a regulatory role in the homeostasis of the BBB.

    “All these studies indicate that exosomes secreted by different cell sources can affect vascular permeability, and in some cases, affect the integrity of BBB, thus playing a regulatory role in the homeostasis of the BBB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Exosomes obtained by genetic engineering have been confirmed to achieve expected transformation and improve targeting ability both in vitro and in vivo.

    “Exosomes obtained by genetic engineering have been confirmed to achieve the expected transformation and improve targeting ability both in vitro and in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    To endow exosomes with stronger targeting properties, genes expressing targeted proteins or peptides are transferred into recipient cells, and the secreted exosomes carry specific homing proteins or peptides such as HER2 and Lamp2.

    “To endow exosomes with stronger targeting properties, the genes expressing these targeted proteins or peptides were transferred into recipient cells, and then the secreted exosomes carried specific homing proteins or peptides, such as HER2 and Lamp2 (Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Biochemical engineering is simpler, faster, and more effective without modification of cells compared with genetic engineering.

    “Compared with genetic engineering, using biochemical engineering to modify exosomes is simpler, faster, and more effective without modification of cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    RVG-targeting exosomes specifically delivered to neurons, oligodendrocytes and microglia of wild-type mice, leading to specific gene knockdown.

    “Through intravenous injection, RVG-targeting exosomes could be specifically delivered to neurons, oligodendrocytes and microglia of wild-type mice, leading to specific gene knockdown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Alvarez-Erviti L Seow Y Yin H Betts C Lakhal S Wood MJ Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes Nat Biotechnol 2011 29 341 5 21423189

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using THLG as a ligand for HER2 significantly enhanced the binding ability of exosomes to target cells, effectively reversing drug resistance and improving the efficiency of cancer treatment.

    “Experimental results found that using THLG as a ligand for HER2 could significantly enhance the binding ability of exosomes to target cells, thereby effectively reversing drug resistance and improving the efficiency of cancer treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liang G et al.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fusing HER2-containing exosomes with phospholipid liposomes by freeze-thaw optimized surface characteristics, reduced immunogenicity, increased stability, and prolonged half-life in blood.

    “This strategy not only optimized the surface characteristics of exosomes, thereby reducing their immunogenicity and increasing their stability, but also prolonged the half-life of exosomes in the blood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Matsuoka T Yashiro M Recent advances in the her2 targeted therapy of gastric cancer World J Clin Cases 2015 3 42 51 25610849 PMC4295218

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    An increasing number of studies have focused on exploiting multiple strategies to engineer natural exosomes to achieve a better target rate.

    “Inspired by this possibility, an increasing number of studies have focused on exploiting multiple strategies to engineer natural exosomes to achieve a better target rate (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exosome-mediated siRNA achieved 62% protein and 60% mRNA inhibition of BACE1, demonstrating therapeutic potential.

    “The powerful protein (62%) and mRNA (60%) inhibition of BACE1 (a therapeutic target for Alzheimer's disease) demonstrated the therapeutic potential of exosome-mediated siRNA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Alvarez-Erviti L Seow Y Yin H Betts C Lakhal S Wood MJ Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes Nat Biotechnol 2011 29 341 5 21423189

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cRGD-Exo containing curcumin was more effective in suppressing inflammatory response and cellular apoptosis in lesion area compared with free curcumin or exosomal treatment alone, indicating active targeting ability to reactive cerebral vascular endothelial cells after ischemia.

    “Compared with free curcumin or exosomal treatment alone, cRGD-Exo containing curcumin (cRGD-Exo-cur) was more effective in suppressing the inflammatory response and cellular apoptosis in the lesion area, indicating the actively targeting ability of engineered exosomes to reactive cerebral vascular endothelial cells after ischemia.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Tian T Zhang HX He CP Fan S Zhu YL Qi C Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy Biomaterials 2018 150 137 49 29040874

      Not checked in the free run.

    • cites [104] Guell K Bix GJ Brain endothelial cell specific integrins and ischemic stroke Expert Rev Neurother 2014 14 1287 92 25262658

      Not checked in the free run.

    • cites [111] Arosio D Casagrande C Advancement in integrin facilitated drug delivery Adv Drug Deliv Rev 2016 97 111 43 26686830

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coupling RVG peptide to MSC-derived exosomes via DOPE-NHS reduced plaque deposition and Aβ level, reduced astrocyte activation, and efficiently accumulated in brains of transgenic APP/PS1 mice.

    “Compared with MSC-Exos, the plaque deposition and Aβ level of the MSC-RVG-Exo-treated group dropped sharply, and the activation of astrocytes was significantly reduced. Functional exosomes efficiently accumulated in the brains of transgenic APP/PS1 mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Cui GH Guo HD Li H Zhai Y Gong ZB Wu J Rvg-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of alzheimer's disease Immun Ageing 2019 16 10 21 31114624 PMC6515654

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insertion of ligand-conjugated PEG-derived phospholipids in exosome membrane allowed exosomes to have higher cell specificity and longer circulation time, which might increase accumulation in target tissues and improve cargo transport efficiency.

    “More importantly, the insertion of ligand-conjugated PEG-derived phospholipids in the exosome membrane allowed the exosomes to have higher cell specificity and longer circulation time, which might increase the accumulation of exosomes in target tissues and improve cargo transport efficiency.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Kooijmans SAA Fliervoet LAL van der Meel R Fens M Heijnen HFG van Bergen En Henegouwen PMP Pegylated and targeted extracellular vesicles display enhanced cell specificity and circulation time J Control Release 2016 224 77 85 26773767

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Genetic engineering processes are complex and costly, and cannot be applied to pre-separated exosomes or natural exosomes existing in body fluids.

    “However, these engineering processes are complex and costly, and most importantly, this method cannot be applied to the pre-separated exosomes or the natural exosomes existing in body fluids.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The GE11 peptide has high affinity for epidermal growth factor receptor (EGFR), a protein abundant in a variety of human epithelial tumors.

    “Ohno S et al. found that the GE11 peptide had high affinity for epidermal growth factor receptor (EGFR), a protein abundant in a variety of human epithelial tumors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Ohno S Takanashi M Sudo K Ueda S Ishikawa A Matsuyama N Systemically injected exosomes targeted to egfr deliver antitumor microrna to breast cancer cells Mol Ther 2013 21 185 91 23032975 PMC3538304

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Exosomes secreted by B lymphocytes can bind antigen-specific class II MHC to inhibit the activation of T cells, indicating the importance of exosomes in antigen presentation in vivo.

    “Therefore, exosomes secreted by B lymphocytes could bind antigen-specific class II MHC to inhibit the activation of T cells, indicating the importance of exosomes in the process of antigen presentation in vivo 101, 102.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [101] Raposo G Nijman HW Stoorvogel W Liejendekker R Harding CV Melief CJ B lymphocytes secrete antigen-presenting vesicles J Exp Med 1996 183 1161 72 8642258 PMC2192324

      Not checked in the free run.

    • cites [102] Zitvogel L Regnault A Lozier A Wolfers J Flament C Tenza D Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes Nat Med 1998 4 594 600 9585234

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Molecular characteristics and regulatory function of exosomes mainly depend on types of cells that secrete them.

    “The molecular characteristics and regulatory function of exosomes mainly depend on the types of cells that secrete them.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In biochemical engineering, temperature, pressure, and salt concentration may cause excessive osmotic pressure, membrane rupture and surface protein denaturation.

    “Nevertheless, in the process of biochemical engineering, it is necessary to consider that temperature, pressure, and salt concentration may cause excessive osmotic pressure, membrane rupture and surface protein denaturation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Changes in exosome surface charge, membrane rigidity and immunogenicity will affect exosome stability, in vivo fate and follow-up therapeutic effects.

    “Changes in exosome surface charge, membrane rigidity and immunogenicity will also affect exosome stability, in vivo fate and follow-up therapeutic effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MSC-exo presented distinct brain migration and homing patterns in various brain pathologies after nasal administration: in focal ischemic stroke model mainly in striatum; in Parkinson's disease model to striatum, midbrain and cerebellum; in Alzheimer's disease model in hippocampus; in healthy brains diffuse and cleared within 24 hours.

    “Perets N et al. determined that MSC-exo presented distinct brain migration and homing patterns in various brain pathologies after nasal administration 72. In a focal ischemic stroke model (via ETH1-1 injection), MSC-exo were mainly distributed in the injection area of the striatum. In the Parkinson's disease model (6-OHDA induced) 126, a large number of MSC-exo migrated to the striatum, as well as”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] Perets N Betzer O Shapira R Brenstein S Angel A Sadan T Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders Nano Lett 2019 19 3422 31 30761901

      Not checked in the free run.

    • cites [126] Talanov SA Oleshko NN Tkachenko MN Sagach VF Pharmacoprotective influences on different links of the mechanism underlying 6-hydroxydopamine-induced degeneration of nigro-striatal dopaminergic neurons Neurophysiology 2006 38 128 33

      Not checked in the free run.

    • cites [127] Eimer WA Vassar R Neuron loss in the 5xfad mouse model of alzheimer's disease correlates with intraneuronal aβ42 accumulation and caspase-3 activation Mol Neurodegener 2013 8 2 23316765 PMC3552866

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IONPs could stimulate expression of therapeutic growth factors in MSCs by activating phosphorylation of c-Jun and JNK; IONPs are biocompatible as they can be assimilated into iron ions and ferritin.

    “Furthermore, IONPs could stimulate the expression of therapeutic growth factors in MSCs by activating the phosphorylation of c-Jun and c-Jun N-terminal kinase (JNK) molecules. IONPs are also biocompatible as they can be assimilated into iron ions and ferritin. 114.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Auerbach M Chertow GM Rosner M Ferumoxytol for the treatment of iron deficiency anemia Expert Rev Hematol 2018 11 829 34 30188740

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Genetic methods are more accurate in obtaining desired products, but process is complicated and costly.

    “Genetic methods are more accurate in obtaining the desired products, but the process is complicated and costly.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exosomes participate in long-distance intercellular communication and promote transfer of proteins, miRNAs and functional mRNA for subsequent protein expression in target cells.

    “Recent studies have shown that exosomes participate in long-distance intercellular communication and promote the transfer of proteins, miRNAs and functional mRNA for subsequent protein expression in target cells 119.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Zomer A Vendrig T Hopmans ES van Eijndhoven M Middeldorp JM Pegtel DM Exosomes: Fit to deliver small rna Commun Integr Biol 2010 3 447 50 21057637 PMC2974077

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to direct delivery of living cells, exosomes have ability to cross BBB easily, showing unique advantages in treatment of brain diseases.

    “Compared to direct delivery of living cells, exosomes have the ability to cross the BBB easily, which shows unique advantages in the treatment of brain diseases 121.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Shao H Chung J Balaj L Charest A Bigner DD Carter BS Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy Nat Med 2012 18 1835 40 23142818 PMC3518564

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical methods such as coincubation, ultrasound, and electroporation cause little damage to exosomes and have little effect on their function.

    “These methods cause little damage to exosomes and have little effect on their function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Gopalan D Pandey A Udupa N Mutalik S Receptor specific, stimuli responsive and subcellular targeted approaches for effective therapy of Alzheimer: Role of surface engineered nanocarriers J Control Release 2020 319 183 200 31866505

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MSC-derived exosomes retain important characteristics of parental MSCs, such as neurite remodeling, immune modulation, angiogenesis promotion, and migration and homing abilities.

    “Several studies have shown that MSC-derived exosomes (MSC-exo) retain important characteristics of their parental MSCs, such as neurite remodeling, immune modulation, angiogenesis promotion, and notably, migration and homing abilities 124, 125.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [124] Zhang Y Chopp M Liu XS Katakowski M Wang X Tian X Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons Mol Neurobiol 2017 54 2659 73 26993303 PMC5028236

      Not checked in the free run.

    • cites [125] Li D Zhang P Yao X Li H Shen H Li X Exosomes derived from mir-133b-modified mesenchymal stem cells promote recovery after spinal cord injury Front Neurosci 2018 12 845 30524227 PMC6262643

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Physical targeting is noninvasive with less damage to exosomes, but complex auxiliary equipment is required for preparation or in vivo guided targeting.

    “Physical targeting is a noninvasive method with less damage to exosomes, but complex auxiliary equipment is required for the preparation process or in vivo guided targeting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Unmodified natural exosomes have problems of low targeting efficiency, short circulating half-life and poor efficacy.

    “Although unmodified natural exosomes have targeting ability, they still have the problems of low targeting efficiency, short circulating half-life and poor efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    MSC-exo not only promoted neuronal survival and angiogenesis but also attenuated peripheral immunosuppression, which supported use of MSC-exo in treatment of stroke.

    “Additionally, MSC-exo not only promoted neuronal survival and angiogenesis but also attenuated peripheral immunosuppression, which supported the use of MSC-exo in the treatment of stroke.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Biochemical methods can effectively control functional structure of exosome surface and density of targeted epitopes, but reactions require multiple biochemical steps, which may impair function of carbohydrates and proteins on exosome membrane.

    “Biochemical methods can effectively control the functional structure of the exosome surface (including unnatural amino acids that prevent peptide degradation) and the density of targeted epitopes, but the reactions require multiple biochemical steps, which may impair the function of carbohydrates and proteins on the exosome membrane.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Accumulation of MSC-exo in pathological brain was highly correlated with neuroinflammatory signals, suggesting exosome migration was triggered by inflammation.

    “Taken together, the accumulation of MSC-exo in the pathological brain was highly correlated with neuroinflammatory signals, suggesting that exosome migration was triggered by inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    If some original surface ligands of exosomes are inactivated, their corresponding signal cascades may not be triggered, thus reducing internalization of exosomes in receptor cells.

    “In the process of engineering, if some of the original surface ligands of exosomes are inactivated, their corresponding signal cascades may not be triggered, thus reducing the internalization of exosomes in receptor cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    All engineering strategies provide attractive prospects for expanding targeting efficiency and therapeutic capacity of exosomes beyond original function.

    “All these engineering strategies provide attractive prospects for expanding the targeting efficiency and therapeutic capacity of exosomes beyond their original function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After allogeneic administration in vivo, exosomes will not block blood vessels or cause significant adverse reactions.

    “After allogeneic administration in vivo, exosomes will not block blood vessels or cause significant adverse reactions 120.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Li Y Cheng Q Hu G Deng T Wang Q Zhou J Extracellular vesicles in mesenchymal stromal cells: A novel therapeutic strategy for stroke Exp Ther Med 2018 15 4067 79 29725359 PMC5920496

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exosomes can be stored at -80 °C for 6 months without degradation, effectively protecting internal soluble molecules including biological factors and nucleic acids.

    “In addition, exosomes can be stored at -80 °C for 6 months without degradation, which can effectively protect internal soluble molecules, including biological factors and nucleic acids 122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Théry C Amigorena S Raposo G Clayton A Isolation and characterization of exosomes from cell culture supernatants and biological fluids Curr Protoc Cell Biol 2006 Chapter 3: Unit 3.22 18228490

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After co-incubation with PC12 cells, Mφ-exo were effectively internalized into neurons and built up on plasma membrane, showing unparalleled accumulation compared to synthetic particles.

    “After co-incubation with the target neuronal cell (PC12 cells), Mϕ-exo were effectively internalized into neurons and then built up on plasma membrane, showing an unparalleled accumulation compared to these synthetic particles 40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Haney MJ Klyachko NL Zhao Y Gupta R Plotnikova EG He Z Exosomes as drug delivery vehicles for parkinson's disease therapy J Control Release 2015 207 18 30 25836593 PMC4430381

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DC-Exo can be directly recognized by primed effector T cells or captured and presented by other DCs to activate naïve T cells, modulating immune system during stroke.

    “DC-Exo can be directly recognized by primed effector T cells or be captured and next presented by other DCs to activate naïve T cells, modulating the immune system during stroke 130.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Zhang B Yin Y Lai RC Lim SK Immunotherapeutic potential of extracellular vesicles Front Immunol 2014 5 518 25374570 PMC4205852

      Not checked in the free run.

75 of 75

  • The paper relies on this without support.

    Administration routes have an important influence on the biodistribution, therapeutic effect and short-term/long-term biological effects of exosomes.

    “In addition to the mentioned characteristics of exosome, routes of administration also have an important influence on the biodistribution, therapeutic effect and short-term/long-term biological effects of exosomes.”

  • The paper relies on this without support.

    The half-life of systemically administered exosomes is too short, ranging from several minutes to a few hours.

    “Although intravenous injection is a widely used method, the half-life index of systemically administered exosomes is still too short, ranging from several minutes to a few hours.”

  • The paper relies on this without support.

    Oral administration has advantages of less fluctuation of drug levels in plasma, good patient compliance and acceptance, and low cost-effectiveness.

    “The main significant advantages of oral administration are 1) less fluctuation of drug levels in plasma, 2) good patient compliance and acceptance, and 3) low cost-effectiveness.”

  • The paper relies on this without support.

    Oral administration of exosomes faces major hurdles including poor bioavailability and first pass metabolism in the small intestine.

    “Although oral administration may have many advantages, there are still some major hurdles in the application of exosomes, such as poor bioavailability and first pass metabolism in the small intestine.”

  • The paper relies on this without support.

    Most orally administered exosomes localize in the small intestine, the unabsorbed part transfers to the colon, a small part (<5%) diffuses in the liver, and exosomes are difficult to spread to the brain.

    “Most of the exosomes were localized in the small intestine, the unabsorbed part was transferred to the colon, a small part (<5%) was diffused in the liver, and exosomes was difficult to spread to the brain.”

  • The paper relies on this without support.

    After purification, the amount of exosomes derived from non-food sources, such as secreted by cells, is not enough to meet oral requirements.

    “After purification, the amount of exosomes derived from non-food sources, such as secreted by cells, is not enough to meet oral requirements.”

  • The paper relies on this without support.

    Certain molecules on the surface of stem cells can play a role in the targeting ability of exosomes.

    “Studies have shown that certain molecules on the surface of stem cells can play a role in the targeting ability of exosomes.”

  • The paper relies on this without support.

    Stem cell-derived exosomes can be delivered to subgranular areas of the hippocampus associated with mood disorders to improve neurogenesis.

    “Stem cell-derived exosomes can be delivered to subgranular areas of the hippocampus associated with mood disorders to improve neurogenesis.”

  • The paper relies on this without support.

    Findings from animal models of engineered exosomes will translate to human patients.

    “Engineered exosomes have great potential in diagnosis, treatment, clinical transformation, but they still face some technical challenges.”

  • The paper relies on this without support.

    The composition of exosomes is not random and each exosome contains specific molecular information.

    “The composition of exosomes is not random, and each exosome contains specific molecular information.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Exosomes can be genetically engineered, chemically surface modified or enzymatically engineered to introduce peptides and proteins to enhance their targeting ability.

    “In addition, exosomes can be genetically engineered, chemically surface modified or enzymatically engineered to introduce peptides and proteins to enhance their targeting ability [42, 83–86].”

    From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [83]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Oral exosome studies are not limited to food-derived exosomes

    Minor

    The paper says current oral-administration research is limited to food-derived exosomes, but it earlier describes an oral-treatment study using exosomes derived from suppressor T cells.

1 of 1

Cites

2 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. [50]Xin H Katakowski M Wang F Qian JY Liu XS Ali MM Microrna cluster mir-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats Stroke 2017 48 747 53 28232590 PMC5330787
  2. [132]Jahangard Y Monfared H Moradi A Zare M Mirnajafi-Zadeh J Mowla SJ Therapeutic effects of transplanted exosomes containing mir-29b to a rat model of alzheimer's disease Front Neurosci 2020 14 564 32625049 PMC7314926
  3. [148]Morishita M Takahashi Y Nishikawa M Sano K Kato K Yamashita T Quantitative analysis of tissue distribution of the b16bl6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice J Pharm Sci 2015 104 705 13 25393546

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Authors
Xu, M., Feng, T., Liu, B., Qiu, F., Xu, Y., Zhao, Y., & Zheng, Y.
Affiliations
  • University of Macau (MO)
  • Macau University of Science and Technology (MO)
Corresponding author
  • Zhao, Yonghua
  • Zheng, Ying
ORCID
Venue
Theranostics
Publisher
Ivyspring International Publisher
Published
2021
Volume
11
Issue
18
Pages
8926-8944
ISSN
1838-7640 (ISSN-L)
DOI
10.7150/thno.62330
PMC
PMC8419041
OpenAlex
W3196376604
Cited by
229
References
154
Citations by year
2026: 26 · 2025: 59 · 2024: 56 · 2023: 57 · 2022: 31
FWCI
11.30
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Theranostics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
engineered exosomes, exosome engineering, extracellular vesicles, cerebrovascular disease, neurodegenerative diseases, blood-brain barrier penetration, targeted delivery, exosome internalization, intercellular communication
MeSH terms
Extracellular Vesicles, Animals, Biological Transport, Blood-Brain Barrier, Cell Communication, Cerebrovascular Disorders, Humans, Protein Engineering, Drug Delivery Systems, Neurodegenerative Diseases, Secretory Vesicles, Exosomes, Bioengineering

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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