A kaleidoscopic view of extracellular vesicles in lysosomal storage disorders

Abstract

Extracellular vesicles (EVs) are a heterogeneous population of stable lipid membrane particles that play a critical role in the regulation of numerous physiological and pathological processes. EV cargo, which includes lipids, proteins, and RNAs including miRNAs, is affected by the metabolic status of the parental cell. Concordantly, abnormalities in the autophagic-endolysosomal pathway, as seen in lysosomal storage disorders (LSDs), can affect EV release as well as EV cargo. LSDs are a group of over 70 inheritable diseases, characterized by lysosomal dysfunction and gradual accumulation of undigested molecules. LSDs are caused by single gene mutations that lead to a deficiency of a lysosomal protein or lipid. Lysosomal dysfunction sets off a cascade of alterations in the endolysosomal pathway that can affect autophagy and alter calcium homeostasis, leading to energy imbalance, oxidative stress, and apoptosis. The pathophysiology of these diseases is very heterogenous, complex, and currently incompletely understood. LSDs lead to progressive multisystemic symptoms that often include neurological deficits. In this review, a kaleidoscopic overview will be given on the roles of EVs in LSDs, from their contribution to pathology and diagnostics to their role as drug delivery vehicles. Furthermore, EV cargo and surface engineering strategies will be discussed to show the potential of EVs in future LSD treatment, both in the context of enzyme replacement therapy, as well as future gene editing strategies like CRISPR/Cas. The use of engineered EVs as drug delivery vehicles may mask therapeutic cargo from the immune system and protect it from degradation, improving circulation time and targeted delivery.

Keywords

Lysosomal storage disorders / extracellular vesicles / autophagy / therapeutics / diagnostics

References

[1] Walkley SU.Secondary lipid accumulation in lysosomal disease.Biochim Biophys Acta2009;1793:726-36 PMCID:PMC4382014

[2] Lamanna WC,Sarrazin S.Secondary storage of dermatan sulfate in Sanfilippo disease.J Biol Chem2011;286:6955-62 PMCID:PMC3044951

[3] Prinetti A,Chiricozzi E,Chigorno V.Secondary alterations of sphingolipid metabolism in lysosomal storage diseases.Neurochem Res2011;36:1654-68

[4] Lieberman AP,Raben N,Walkley SU.Autophagy in lysosomal storage disorders.Autophagy2012;8:719-30 PMCID:PMC3378416

[5] Köse S,Uçkan Çetinkaya D.Stem cell applications in lysosomal storage disorders: progress and ongoing challenges. In: Turksen K, editor. Cell biology and translational medicine, Volume 14. Cham: Springer International Publishing; 2021. p. 135-62.

[6] Platt FM,van der Spoel AC.The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction.J Cell Biol2012;199:723-34 PMCID:PMC3514785

[7] Platt FM,Davidson BL,Tifft CJ.Lysosomal storage diseases.Nat Rev Dis Primers2018;4:27

[8] Marques ARA.Lysosomal storage disorders - challenges, concepts and avenues for therapy: beyond rare diseases.J Cell Sci2019;132:jcs221739

[9] Parenti G,Ballabio A.Lysosomal storage diseases: from pathophysiology to therapy.Annu Rev Med2015;66:471-86

[10] Meikle PJ,Clague AE.Prevalence of lysosomal storage disorders.JAMA1999;281:249-54

[11] Fuller M,Hopwood JJ.Epidemiology of lysosomal storage diseases: an overview. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 2.

[12] Mehta A,Sunder-Plassmann G.Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis; 2006.

[13] Stone WL,Master SR.Gaucher disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.

[14] Grabowski GA,Osiecki KM,Legler G.Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine.Am J Hum Genet1985;37:499-510 PMCID:PMC1684582

[15] van den Broek BTA,Hegeman CV.Hurdles in treating Hurler disease: potential routes to achieve a “real” cure.Blood Adv2020;4:2837-49 PMCID:PMC7322951

[16] Li M.Enzyme replacement therapy: a review and its role in treating lysosomal storage diseases.Pediatr Ann2018;47:e191-7

[17] Kishnani PS,Muldowney L.Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.Mol Genet Metab2016;117:66-83

[18] Safary A,Mousavi R,Rafi MA.Enzyme replacement therapies: What is the best option?.Bioimpacts2018;8:153-7 PMCID:PMC6128977

[19] Solomon M.Lysosomal enzyme replacement therapies: historical development, clinical outcomes, and future perspectives.Adv Drug Deliv Rev2017;118:109-34 PMCID:PMC5828774

[20] Aldenhoven M,Bonney D.Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.Biol Blood Marrow Transplant2015;21:1106-9

[21] Guffon N,Pangaud N.Long term disease burden post-transplantation: three decades of observations in 25 Hurler patients successfully treated with hematopoietic stem cell transplantation (HSCT).Orphanet J Rare Dis2021;16:60 PMCID:PMC7847591

[22] Selvanathan A,Wilson C,Shaw PJ.Effectiveness of early hematopoietic stem cell transplantation in preventing neurocognitive decline in mucopolysaccharidosis type II: a case series. In: Morava E, Baumgartner M, Patterson M, Rahman S, Zschocke J, Peters V, editors. JIMD Reports, Volume 41. Berlin: Springer Berlin Heidelberg; 2018. p. 81-9. PMCID:PMC6122046

[23] Mynarek M,Albert MH.Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.Bone Marrow Transplant2012;47:352-9

[24] Beschle J,Kehrer C.Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy.Mol Cell Pediatr2020;7:12 PMCID:PMC7483683

[25] Wright MD,DeRenzo A,Escolar ML.Developmental outcomes of cord blood transplantation for Krabbe disease: a 15-year study.Neurology2017;89:1365-72 PMCID:PMC5649761

[26] Aerts JM,Boot RG,Maas M.Substrate reduction therapy of glycosphingolipid storage disorders.J Inherit Metab Dis2006;29:449-56

[27] Hughes DA,Shankar SP.Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.J Med Genet2017;54:288-96 PMCID:PMC5502308

[28] Nagree MS,McKillop WM.An update on gene therapy for lysosomal storage disorders.Expert Opin Biol Ther2019;19:655-70

[29] Phinney DG.Mesenchymal stem cells as cellular vectors for pediatric neurological disorders.Brain Res2014;1573:92-107 PMCID:PMC4103155

[30] Pittenger MF,Péault BM,Hare JM.Mesenchymal stem cell perspective: cell biology to clinical progress.NPJ Regen Med2019;4:22 PMCID:PMC6889290

[31] Jackson M,Martin E,Gronthos S.Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells.Mol Genet Metab2015;114:584-93

[32] Hawkins-Salsbury JA,Sands MS.Combination therapies for lysosomal storage disease: Is the whole greater than the sum of its parts?.Hum Mol Genet2011;20:R54-60 PMCID:PMC3095053

[33] Koç ON,Aubourg P.Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.Exp Hematol1999;27:1675-81

[34] Meuleman N,Tondreau T.Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report.Haematologica2008;93:e11-3

[35] de Windt TS,Slaper-Cortenbach IC.Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons.Stem Cells2017;35:256-64

[36] Yáñez-Mó M,Andreu Z.Biological properties of extracellular vesicles and their physiological functions.J Extracell Vesicles2015;4:27066 PMCID:PMC4433489

[37] de Jong OG,Chen Y.Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes.J Extracell Vesicles2012;1:18396 PMCID:PMC3760650

[38] Saint-Pol J,Duban-Deweer S,Karamanos Y.Targeting and crossing the blood-brain barrier with extracellular vesicles.Cells2020;9:851 PMCID:PMC7226770

[39] Banks WA,Bullock KM,Ludwig N.Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation.Int J Mol Sci2020;21:4407 PMCID:PMC7352415

[40] Liu S,Chandra S.Extracellular vesicles: emerging tools as therapeutic agent carriers.Acta Pharm Sin B2022;12:3822-42 PMCID:PMC9532556

[41] Abasolo I,Moltó-Abad M.Nanotechnology-based approaches for treating lysosomal storage disorders, a focus on Fabry disease.Wiley Interdiscip Rev Nanomed Nanobiotechnol2021;13:e1684

[42] Schuh RS,Teixeira HF.Nanotechnology applied to treatment of mucopolysaccharidoses.Expert Opin Drug Deliv2016;13:1709-18

[43] Grosso A, Parlanti G, Mezzena R, Cecchini M. Current treatment options and novel nanotechnology-driven enzyme replacement strategies for lysosomal storage disorders.Adv Drug Deliv Rev2022;188:114464

[44] Baixauli F,Mittelbrunn M.Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness.Front Immunol2014;5:403 PMCID:PMC4138502

[45] Zaborowski MP,Breakefield XO.Extracellular vesicles: composition, biological relevance, and methods of study.Bioscience2015;65:783-97 PMCID:PMC4776721

[46] Varderidou-Minasian S.Mesenchymal stromal/stem cell-derived extracellular vesicles in tissue repair: challenges and opportunities.Theranostics2020;10:5979-97 PMCID:PMC7254996

[47] Théry C,Aikawa E.Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles2018;7:1535750 PMCID:PMC6322352

[48] Thakur BK,Becker A.Double-stranded DNA in exosomes: a novel biomarker in cancer detection.Cell Res2014;24:766-9 PMCID:PMC4042169

[49] Coutinho MF,Alves S.A shortcut to the lysosome: the mannose-6-phosphate-independent pathway.Mol Genet Metab2012;107:257-66

[50] Fedele AO,Kamei M.Lysosomal N-acetyltransferase interacts with ALIX and is detected in extracellular vesicles.Biochim Biophys Acta Mol Cell Res2018;1865:1451-64

[51] Li Y,Li Q.EV-origin: Enumerating the tissue-cellular origin of circulating extracellular vesicles using exLR profile.Comput Struct Biotechnol J2020;18:2851-9 PMCID:PMC7588739

[52] Emmanouilidou E,Roumeliotis T.Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival.J Neurosci2010;30:6838-51 PMCID:PMC3842464

[53] Trotta T,Cianciulli A,Di Benedetto A.Microglia-derived extracellular vesicles in Alzheimer’s Disease: a double-edged sword.Biochem Pharmacol2018;148:184-92

[54] Ananbeh H,Kupcova Skalnikova H.Emerging roles of exosomes in huntington’s disease.Int J Mol Sci2021;22:4085 PMCID:PMC8071291

[55] Tancini B,Sagini K.Insight into the role of extracellular vesicles in lysosomal storage disorders.Genes (Basel)2019;10:510 PMCID:PMC6679199

[56] Navarro-Romero A,Martinez-Vicente M.The emerging role of the lysosome in parkinson’s disease.Cells2020;9:2399 PMCID:PMC7692401

[57] Almeida MF,Kinsey ST.Endosomal-lysosomal dysfunction in metabolic diseases and Alzheimer’s disease. Metabolic and bioenergetic drivers of neurodegenerative disease: neurodegenerative disease research and commonalities with metabolic diseases. Elsevier; 2020. p. 303-24. PMCID:PMC8428780

[58] Porro C,Lofrumento DD,Trotta T.The multiple roles of exosomes in Parkinson’s disease: an overview.Immunopharmacol Immunotoxicol2019;41:469-76

[59] Gassart A, Géminard C, Hoekstra D, Vidal M. Exosome secretion: the art of reutilizing nonrecycled proteins?.Traffic2004;5:896-903

[60] Bernardi S.Extracellular vesicles: from biomarkers to therapeutic tools.Biology (Basel)2020;9:258 PMCID:PMC7564466

[61] Parada N,Georges N.Camouflage strategies for therapeutic exosomes evasion from phagocytosis.J Adv Res2021;31:61-74 PMCID:PMC8240105

[62] de Jong OG,Murphy DE.Drug delivery with extracellular vesicles: from imagination to innovation.Acc Chem Res2019;52:1761-70 PMCID:PMC6639984

[63] Kooijmans SAA,van der Meel R.PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time.J Control Release2016;224:77-85

[64] Wiklander OP,O'Loughlin A.Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting.J Extracell Vesicles2015;4:26316 PMCID:PMC4405624

[65] Yim WW.Lysosome biology in autophagy.Cell Discov2020;6:6 PMCID:PMC7010707

[66] Schröder BA,Hasilik A.The proteome of lysosomes.Proteomics2010;10:4053-76

[67] Chang NC.Autophagy and Stem Cells: self-eating for self-renewal. frontiers in cell and developmental Biology 2020;8. PMCID:PMC7065261

[68] Song HY,Yarmishyn AA.Generation of GLA-knockout human embryonic stem cell lines to model autophagic dysfunction and exosome secretion in fabry disease-associated hypertrophic cardiomyopathy.Cells2019;8:327 PMCID:PMC6523555

[69] Bartolomeo R,De Leonibus C.mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy.J Clin Invest2017;127:3717-29 PMCID:PMC5617676

[70] Brown RA,Srikanth MP.mTOR hyperactivity mediates lysosomal dysfunction in Gaucher’s disease iPSC-neuronal cells.Dis Model Mech2019;12 PMCID:PMC6826018

[71] Gao J,de Assuncao TM.Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis.J Hepatol2020;73:1144-54 PMCID:PMC7572579

[72] Skotland T,Sandvig K.An emerging focus on lipids in extracellular vesicles.Adv Drug Deliv Rev2020;159:308-21

[73] Gurung S,Touramanidou L.The exosome journey: from biogenesis to uptake and intracellular signalling.Cell Commun Signal2021;19:47 PMCID:PMC8063428

[74] Hessvik NP,Brech A.PIKfyve inhibition increases exosome release and induces secretory autophagy.Cell Mol Life Sci2016;73:4717-37

[75] Miranda AM,Xu Y.Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures.Nat Commun2018;9:291 PMCID:PMC5773483

[76] Strauss K,Runz H.Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease.J Biol Chem2010;285:26279-88 PMCID:PMC2924046

[77] Ilnytska O,Lai K,Dobrowolski R.Lysobisphosphatidic acid (LBPA) enrichment promotes cholesterol egress via exosomes in Niemann Pick type C1 deficient cells.Biochim Biophys Acta Mol Cell Biol Lipids2021;1866:158916 PMCID:PMC8038758

[78] van de Vlekkert D,Nguyen XX.Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis.Sci Adv2019;5:eaav3270 PMCID:PMC6636989

[79] D’Auria L,Ward E.Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe's disease.PLoS One2017;12:e0178103 PMCID:PMC5439731

[80] Bhat OM,Yuan X.Arterial medial calcification through enhanced small extracellular vesicle release in smooth muscle-specific asah1 gene knockout mice.Sci Rep2020;10:1645 PMCID:PMC6997457

[81] Reiter CR,Kwak A.The pathogenic sphingolipid psychosine is secreted in extracellular vesicles in the brain of a mouse model of krabbe disease.ASN Neuro2022;14:17590914221087817 PMCID:PMC8943320

[82] Pituch KC,Lopez-Rosas A.Dysfunction of platelet-derived growth factor receptor α (PDGFRα) represses the production of oligodendrocytes from arylsulfatase a-deficient multipotential neural precursor cells.J Biol Chem2015;290:7040-53 PMCID:PMC4358127

[83] Chen FW,Ioannou YA.Cyclodextrin induces calcium-dependent lysosomal exocytosis.PLoS One2010;5:e15054 PMCID:PMC2993955

[84] Canonico B,Salucci S.Defective autophagy, mitochondrial clearance and lipophagy in niemann-pick type B lymphocytes.PLoS One2016;11:e0165780 PMCID:PMC5087958

[85] Alvarez-Erviti L,Schapira AH.Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission.Neurobiol Dis2011;42:360-7 PMCID:PMC3107939

[86] Vingtdeux V,Loyens A.Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies.J Biol Chem2007;282:18197-205

[87] Raben N,Baum R.Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.Autophagy2010;6:1078-89 PMCID:PMC3039718

[88] Spampanato C,Li L.Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease.EMBO Mol Med2013;5:691-706 PMCID:PMC3662313

[89] Gatto F,Tarallo A.AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease.Sci Rep2017;7:15089 PMCID:PMC5678083

[90] Manjithaya R.Autophagy: a broad role in unconventional protein secretion?.Trends Cell Biol2011;21:67-73 PMCID:PMC3025270

[91] Klein D,Fewou SN.Exocytosis of storage material in a lysosomal disorder.Biochem Biophys Res Commun2005;327:663-7

[92] Yogalingam G,van de Vlekkert D.Neuraminidase 1 is a negative regulator of lysosomal exocytosis.Dev Cell2008;15:74-86 PMCID:PMC2664108

[93] Hastings C,Liu B.Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis.Orphanet J Rare Dis2019;14:228 PMCID:PMC6805667

[94] Pergande MR,George D.Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice.Lipids Health Dis2022;21:32 PMCID:PMC8962106

[95] Batzios SP,Papakonstantinou E.Extracellular matrix components: an intricate network of possible biomarkers for lysosomal storage disorders?.FEBS Lett2013;587:1258-67

[96] Feltri ML,Favret J,Wrabetz L.Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy.Glia2021;69:2309-31 PMCID:PMC8502241

[97] Galvan C,Cristofani F,Ledesma MD.Anomalous surface distribution of glycosyl phosphatidyl inositol-anchored proteins in neurons lacking acid sphingomyelinase.Mol Biol Cell2008;19:509-22 PMCID:PMC2230584

[98] Koike T,Taniguchi M.Decreased membrane fluidity and unsaturated fatty acids in Niemann-Pick disease type C fibroblasts.BBA-Mol Basis Dis1998;1406:327-35

[99] Keller S,Rupp AK,Altevogt P.Body fluid derived exosomes as a novel template for clinical diagnostics.J Transl Med2011;9:86 PMCID:PMC3118335

[100] Lässer C,Ekström K.Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages.J Transl Med2011;9:9 PMCID:PMC3033821

[101] Liu H,Pang Q,Yan X.Single-particle analysis of tear fluid reveals abundant presence of tissue factor-exposing extracellular vesicles with strong coagulation activity.Talanta2022;239:123089

[102] Nielsen JE,Vestergård K.Shotgun-based proteomics of extracellular vesicles in Alzheimer’s disease reveals biomarkers involved in immunological and coagulation pathways.Sci Rep2021;11:18518 PMCID:PMC8445922

[103] Upadhya R.Extracellular vesicles for the diagnosis and treatment of parkinson’s disease.Aging Dis2021;12:1438-50 PMCID:PMC8407884

[104] Zhou H,Vogt RF.Newborn bloodspot screening for lysosomal storage disorders.J Pediatr2011;159:7-13.e1

[105] Wang RY,Watson MS.ACMG Work Group on Diagnostic confirmation of lysosomal storage diseaseslysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.Genet Med2011;13:457-84

[106] Puentes-Tellez MA,Garzón-Jaramillo RG.A perspective on research, diagnosis, and management of lysosomal storage disorders in Colombia.Heliyon2020;6:e03635 PMCID:PMC7113438

[107] Han JS,Jin JQ.Tear-derived exosome proteins are increased in patients with thyroid eye disease.Int J Mol Sci2021;22:1115 PMCID:PMC7866068

[108] van den Broek BTA,Achterberg JA.Longitudinal analysis of ocular disease in children with mucopolysaccharidosis i after hematopoietic cell transplantation.Biol Blood Marrow Transplant2020;26:928-35

[109] Gelb MH.Newborn screening for lysosomal storage diseases: methodologies, screen positive rates, normalization of datasets, second-tier tests, and post-analysis tools.Int J Neonatal Screen2018;4:23 PMCID:PMC6419971

[110] Metakids. Welke ziekten zitten er in de hielprik? Available from: https://www.metakids.nl/metabole-ziekten-in-de-hielprik/ [Last accessed on 28 Dec 2022].

[111] Iyer NS,Ferreira CR,Al-Kouatly HB.Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: a systematic review.Clin Genet2021;100:493-503

[112] Keller S,Stoeck A.CD24 is a marker of exosomes secreted into urine and amniotic fluid.Kidney Int2007;72:1095-102

[113] Ebert B.Isolation and characterization of amniotic fluid-derived extracellular vesicles for biomarker discovery. In: Levy B, editor. Prenatal Diagnosis. New York: Springer; 2019. p. 287-94.

[114] Levstek T,Holcar M.Urinary extracellular vesicles and their mirna cargo in patients with fabry nephropathy.Genes (Basel)2021;12:1057 PMCID:PMC8305897

[115] Del Pino M,Bernabéu AÁ.Fabry nephropathy: an evidence-based narrative review.Kidney Blood Press Res2018;43:406-21

[116] Tatiana S,Darya K.Altered level of plasma exosomes in patients with Gaucher disease.Eur J Med Genet2020;63:104038

[117] Lo Curto A,Costa MA.Can Be miR-126-3p a biomarker of premature aging?.Cells2021;10:356 PMCID:PMC7915347

[118] Zahran AM,El-Deek SE.Oxidative stress, trace elements, and circulating microparticles in patients with Gaucher disease before and after enzyme replacement therapy.Clin Appl Thromb Hemost2015;21:58-65

[119] Moyano AL,Boullerne AI.Sulfatides in extracellular vesicles isolated from plasma of multiple sclerosis patients.J Neurosci Res2016;94:1579-87

[120] Krämer-Albers EM,Tenzer S.Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons?.Proteomics Clin Appl2007;1:1446-61

[121] Best MG,Sol N.RNA sequencing and swarm intelligence-enhanced classification algorithm development for blood-based disease diagnostics using spliced blood platelet RNA.Nat Protoc2019;14:1206-34

[122] Best MG,In 't Veld SGJG.Swarm intelligence-enhanced detection of non-small-cell lung cancer using tumor-educated platelets.Cancer Cell2017;32:238-252.e9 PMCID:PMC6381325

[123] Sol N,Veld SGI'.Blood platelet RNA enables the detection of multiple sclerosis.Mult Scler J Exp Transl Clin2020;6:2055217320946784 PMCID:PMC7418262

[124] Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles.Nat Rev Mol Cell Biol2022;23:369-82

[125] Kumari A,Yadav SC.Biodegradable polymeric nanoparticles based drug delivery systems.Colloids Surf B Biointerfaces2010;75:1-18

[126] Sahay G,Alabi C.Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling.Nat Biotechnol2013;31:653-8 PMCID:PMC3814166

[127] Flanagan M,Gan Q.Umbilical mesenchymal stem cell-derived extracellular vesicles as enzyme delivery vehicle to treat Morquio A fibroblasts.Stem Cell Res Ther2021;12:276 PMCID:PMC8101245

[128] Seras-Franzoso J,Corchero JL.Extracellular vesicles from recombinant cell factories improve the activity and efficacy of enzymes defective in lysosomal storage disorders.J Extracell Vesicles2021;10:e12058 PMCID:PMC7953474

[129] Kooijmans SAA,Schiffelers RM.Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design.Adv Drug Deliv Rev2021;173:252-78

[130] Heusermann W,Trojer D.Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER.J Cell Biol2016;213:173-84 PMCID:PMC5084269

[131] Bonsergent E.Content release of extracellular vesicles in a cell-free extract.FEBS Lett2019;593:1983-92

[132] Coulson-Thomas VJ,Kao WW.Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice.Stem Cells2013;31:2116-26 PMCID:PMC3812352

[133] Lai RC,Lee MM.Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.Stem Cell Res2010;4:214-22

[134] Haney MJ,Harrison EB,Kabanov AV.TPP1 delivery to lysosomes with extracellular vesicles and their enhanced brain distribution in the animal model of batten disease.Adv Healthc Mater2019;8:e1801271 PMCID:PMC6584948

[135] Iglesias DM,Taranta A.Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro.PLoS One2012;7:e42840 PMCID:PMC3418268

[136] Thoene J,Witcher M.In vitro correction of disorders of lysosomal transport by microvesicles derived from baculovirus-infected Spodoptera cells.Mol Genet Metab2013;109:77-85

[137] Thoene JG,Mullet J.Microvesicle delivery of a lysosomal transport protein to ex vivo rabbit cornea.Mol Genet Metab Rep2020;23:100587 PMCID:PMC7138922

[138] Haney MJ,Jin YS.Extracellular vesicles as drug carriers for enzyme replacement therapy to treat CLN2 batten disease: optimization of drug administration routes.Cells2020;9:1273 PMCID:PMC7290714

[139] Luan X,Myers I,Yuan H.Engineering exosomes as refined biological nanoplatforms for drug delivery.Acta Pharmacol Sin2017;38:754-63 PMCID:PMC5520184

[140] Li K,Huang H.Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages.J Nanobiotechnology2022;20:38 PMCID:PMC8771624

[141] Sly WS,Grubb JH.Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors.Proc Natl Acad Sci USA2006;103:15172-7 PMCID:PMC1622795

[142] Roefs MT,Brans MAD.Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesiclesFront Pharmacol2022;13:1052091 PMCID:PMC9729535

[143] Hoshino A,Shen TL.Tumour exosome integrins determine organotropic metastasis.Nature2015;527:329-35 PMCID:PMC4788391

[144] Park EJ,Soe ZY.Exosomal regulation of lymphocyte homing to the gut.Blood Adv2019;3:1-11 PMCID:PMC6325302

[145] Perez-Hernandez D,Jorge I.The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes.J Biol Chem2013;288:11649-61 PMCID:PMC3636856

[146] Elsharkasy OM,Hagey DW.Extracellular vesicles as drug delivery systems: Why and how?.Adv Drug Deliv Rev2020;159:332-43

[147] Lennaárd AJ,Wiklander RJ,Wiklander OPB.Optimised electroporation for loading of extracellular vesicles with doxorubicin.Pharmaceutics2021;14:38 PMCID:PMC8780628

[148] Dooley K,Xu K.A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.Mol Ther2021;29:1729-43 PMCID:PMC8116569

[149] Gupta D,Görgens A.Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles.Nat Biomed Eng2021;5:1084-98

[150] Silva AM,Gunnarsson A.Quantification of protein cargo loading into engineered extracellular vesicles at single-vesicle and single-molecule resolution.J Extracell Vesicles2021;10:e12130 PMCID:PMC8329990

[151] Yim N,Choi K.Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module.Nat Commun2016;7:12277 PMCID:PMC4961865

[152] Wang Q,Kadungure T,Zhang H.ARMMs as a versatile platform for intracellular delivery of macromolecules.Nat Commun2018;9:960 PMCID:PMC5840177

[153] Do MA,Brown A,Lu B.Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles.Sci Rep2019;9:17274 PMCID:PMC6872767

[154] Hasilik A.The early and late processing of lysosomal enzymes: proteolysis and compartmentation.Experientia1992;48:130-51

[155] Youn SW,Kim YM.Modification of cardiac progenitor cell-derived exosomes by miR-322 provides protection against myocardial infarction through Nox2-dependent angiogenesis.Antioxidants (Basel)2019;8:18 PMCID:PMC6356993

[156] Sun D,Xiang X.A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes.Mol Ther2010;18:1606-14 PMCID:PMC2956928

[157] Wei H,Wang S.A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro.Int J Nanomedicine2019;14:8603-10 PMCID:PMC6830377

[158] Escudier B,Chaput N.Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.J Transl Med2005;3:10 PMCID:PMC554765

[159] Li Z,Wei M.In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9.Nano Lett2019;19:19-28

[160] Lloyd-Evans E,He X.Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.Nat Med2008;14:1247-55

[161] Canfrán-Duque A,Quintana-Portillo R.Curcumin promotes exosomes/microvesicles secretion that attenuates lysosomal cholesterol traffic impairment.Mol Nutr Food Res2014;58:687-97

[162] Lu B,Flojo R,Bengford D.Exosome- and extracellular vesicle-based approaches for the treatment of lysosomal storage disorders.Adv Drug Deliv Rev2022;188:114465

[163] Belhadj Z,Deng H.A combined “eat me/don’t eat me” strategy based on extracellular vesicles for anticancer nanomedicine.J Extracell Vesicles2020;9:1806444 PMCID:PMC7480498

[164] Komuro H,Aminova S.Engineering extracellular vesicles to target pancreatic tissue in vivo.Nanotheranostics2021;5:378-90 PMCID:PMC8077969

[165] Kamerkar S,Sugimoto H.Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.Nature2017;546:498-503 PMCID:PMC5538883

[166] Kieseier BC,Goebel HH.The monocyte-macrophage system is affected in lysosomal storage diseases: an immunoelectron microscopic study.Acta Neuropathol1997;94:359-62

[167] Limoni SK,Moazzeni SM,Salimi F.Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells.Appl Biochem Biotechnol2019;187:352-64

[168] Gomez-Ospina N,Mostrel N.Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I.Nat Commun2019;10:4045 PMCID:PMC6731271

[169] Paquet D,Chen A.Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9.Nature2016;533:125-9

[170] Hsu PD,Zhang F.Development and applications of CRISPR-Cas9 for genome engineering.Cell2014;157:1262-78 PMCID:PMC4343198

[171] Gaudelli NM,Rees HA.Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage.Nature2017;551:464-71 PMCID:PMC5726555

[172] Komor AC,Packer MS,Liu DR.Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.Nature2016;533:420-4 PMCID:PMC4873371

[173] Kim YB,Levy JM,Zhao KT.Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions.Nat Biotechnol2017;35:371-6 PMCID:PMC5388574

[174] Anzalone AV,Davis JR.Search-and-replace genome editing without double-strand breaks or donor DNA.Nature2019;576:149-57 PMCID:PMC6907074

[175] Scholefield J.Prime editing - an update on the field.Gene Ther2021;28:396-401 PMCID:PMC8376635

[176] Schene IF,Oka R.Prime editing for functional repair in patient-derived disease models.Nat Commun2020;11:5352 PMCID:PMC7584657

[177] Liang Y,Wang J.Cell-derived extracellular vesicles for CRISPR/Cas9 delivery: engineering strategies for cargo packaging and loading.Biomater Sci2022;10:4095-106

[178] Simhadri VL,McMahon S,Jiang H.Prevalence of pre-existing antibodies to CRISPR-associated nuclease Cas9 in the USA population.Mol Ther Methods Clin Dev2018;10:105-12 PMCID:PMC6070699

[179] Gee P,Okuzaki Y.Extracellular nanovesicles for packaging of CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping.Nat Commun2020;11:1334 PMCID:PMC7070030

[180] Meyer C,Stickney Z,Marriott G.Pseudotyping exosomes for enhanced protein delivery in mammalian cells.Int J Nanomedicine2017;12:3153-70 PMCID:PMC5402897

[181] Tomás HA,Rodrigues AF,Carrondo MJT.Improved GaLV-TR glycoproteins to pseudotype lentiviral vectors: impact of viral protease activity in the production of LV pseudotypes.Mol Ther Methods Clin Dev2019;15:1-8 PMCID:PMC6742969

[182] Vargas A,Éthier-Chiasson M.Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia.FASEB J2014;28:3703-19

[183] Prada I.Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets.Int J Mol Sci2016;17:1296 PMCID:PMC5000693

[184] Ye Y,Xie F.An engineered exosome for delivering sgRNA: Cas9 ribonucleoprotein complex and genome editing in recipient cells.Biomater Sci2020;8:2966-76

[185] Osteikoetxea X,Lázaro-Ibáñez E.Engineered Cas9 extracellular vesicles as a novel gene editing tool.J Extracell Vesicles2022;11:e12225 PMCID:PMC9117459

[186] Lener T,Aigner L.Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper.J Extracell Vesicles2015;4:30087 PMCID:PMC4698466