Skip to main content

Advertisement

SpringerLink
Log in

Exosomes: cell-created drug delivery systems

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Exosomes are 40- to 100- nm cell-originated vesicles derived from endocytic compartments that are released into almost all biological fluids. Exosomes are cell-created vesicles that inherit identical phospholipid membrane, explaining a wide application of electroporation as a technique for exosomes loading with exogenous cargoes. Another way of loading exosomes with therapeutic cargo is to overexpress a certain gene in exosome-donor cells or treat cell line with drug of interest that later will be gently enveloped into vesicles based on the process of EV biogenesis. Similarly, to visualize siRNA loading into exosomes as well as the exosomal product delivery to recipient cells, we have conducted an experiment where chemical-based exosome transfection was used. In this review, we discuss different ways of extracellular vesicle loading with exogenous cargoes and their advantages/limitations as well as novel alternative techniques of substance incorporation into nanoparticles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ncRNAs:

Noncoding ribonucleic acid

mRNA:

Messenger RNAs

DNA:

Deoxyribonucleic acids

MVBs:

Multivesicular bodies

miRNAs:

MicroRNAs

siRNA:

Small (or short) interfering RNA

RVG:

Rabies viral glycoprotein

EVs:

Extracellular vesicles

MV:

Microvesicles

CML:

Chronic myelogenous leukemia

MAPK1:

Mitogen-activated protein kinase 1

MAEC:

Mouse-aortic endothelial cell

HuR:

Human antigen R

EXPLORs:

Exosomes for protein loading via optically reversible protein–protein interactions

CRY2:

Cryptochrome 2

CIB1:

CRY-interacting basic-helix-loop-helix1

References

  1. Pan BT, Johnstone R (1984) Selective externalization of the transferrin receptor by sheep reticulocytes in vitro. Response to ligands and inhibitors of endocytosis. J Biol Chem 259:9776–9782

    CAS  PubMed  Google Scholar 

  2. Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–978

    Article  CAS  PubMed  Google Scholar 

  3. Zhang J, Li S, Li L, Li M, Guo C, Yao J, Mi S (2015) Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteom Bioinform 13:17–24. https://doi.org/10.1016/j.gpb.2015.02.001

    Article  CAS  Google Scholar 

  4. Lotvall J, Valadi H (2007) Cell to cell signalling via exosomes through esRNA. Cell Adhes Migr 1:156–158

    Article  Google Scholar 

  5. Zomer A, Vendrig T, Hopmans ES, van Eijndhoven M, Middeldorp JM, Pegtel DM (2010) Exosomes: fit to deliver small RNA. Commun Integr Biol 3:447–450. https://doi.org/10.4161/cib.3.5.12339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920. https://doi.org/10.1016/j.jprot.2010.06.006

    Article  CAS  PubMed  Google Scholar 

  7. Banizs AB, Huang T, Dryden K, Berr SS, Stone JR, Nakamoto RK, Shi W, He J (2014) In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery. Int J Nanomed 9:4223–4230. https://doi.org/10.2147/IJN.S64267

    Article  CAS  Google Scholar 

  8. Yamashita T, Takahashi Y, Takakura Y (2018) Possibility of exosome-based therapeutics and challenges in production of exosomes eligible for therapeutic application. Biol Pharm Bull 41:835–842. https://doi.org/10.1248/bpb.b18-00133

    Article  CAS  PubMed  Google Scholar 

  9. Huang T, Deng CX (2019) Current progresses of exosomes as cancer diagnostic and prognostic biomarkers. Int J Biol Sci 15:1–11. https://doi.org/10.7150/ijbs.27796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Suntres ZE, Smith MG, Momen-Heravi F, Hu J, Zhang X, Wu Y, Zhu H, Wang J, Zhou J, Kuo PW (2013) Therapeutic uses of exosomes. J Exosomes Microvesicles 1:1–8

    Google Scholar 

  11. Asadirad A, Hashemi SM, Baghaei K, Ghanbarian H, Mortaz E, Zali MR, Amani D (2019) Phenotypical and functional evaluation of dendritic cells after exosomal delivery of miRNA-155. Life Sci 219:152–162

    Article  CAS  PubMed  Google Scholar 

  12. Kyuno D, Zhao K, Bauer N, Ryschich E, Zoller M (2019) Therapeutic targeting cancer-initiating cell markers by exosome miRNA: efficacy and functional consequences exemplified for claudin7 and EpCAM. Transl Oncol 12:191–199

    Article  PubMed  Google Scholar 

  13. Pomatto MAC, Bussolati B, D’Antico S, Ghiotto S, Tetta C, Brizzi MF, Camussi G (2019) Improved loading of plasma-derived extracellular vesicles to encapsulate antitumor miRNAs. Mol Ther Methods Clin Dev 13:133–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Faruqu FN, Xu L, Al-Jamal KT (2018) Preparation of exosomes for siRNA delivery to cancer cells. J Vis Exp 142:e58814

    Google Scholar 

  15. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546:498–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, Inskoe E, Piroyan A, Sokolsky M, Okolie O, Hingtgen SD, Kabanov AV, Batrakova EV (2016) Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomed Nanotechnol Biol Med 12:655–664

    Article  CAS  Google Scholar 

  17. Ma T, Chen Y (2018) MicroRNA-132, delivered by mesenchymal stem cell-derived exosomes, promote angiogenesis in myocardial infarction. Stem cells Int 2018:3290372

    PubMed  PubMed Central  Google Scholar 

  18. Luan X, Sansanaphongpricha K, Myers I, Chen H, Yuan H, Sun D (2017) Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin 38:754–763. https://doi.org/10.1038/aps.2017.12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345. https://doi.org/10.1038/nbt.1807

    Article  CAS  PubMed  Google Scholar 

  20. Cooper JM, Wiklander PB, Nordin JZ, Al-Shawi R, Wood MJ, Vithlani M, Schapira AH, Simons JP, El-Andaloussi S, Alvarez-Erviti L (2014) Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord 29:1476–1485. https://doi.org/10.1002/mds.25978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lunavat TR, Jang SC, Nilsson L, Park HT, Repiska G, Lasser C, Nilsson JA, Gho YS, Lotvall J (2016) RNAi delivery by exosome-mimetic nanovesicles—implications for targeting c-Myc in cancer. Biomaterials 102:231–238. https://doi.org/10.1016/j.biomaterials.2016.06.024

    Article  CAS  PubMed  Google Scholar 

  22. Greco KA, Franzen CA, Foreman KE, Flanigan RC, Kuo PC, Gupta GN (2016) PLK-1 silencing in bladder cancer by siRNA delivered with exosomes. Urology 91(241):e1–e7. https://doi.org/10.1016/j.urology.2016.01.028

    Article  Google Scholar 

  23. Lamichhane TN, Raiker RS, Jay SM (2015) Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery. Mol Pharm 12:3650–3657. https://doi.org/10.1021/acs.molpharmaceut.5b00364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kooijmans SA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJ, Schiffelers RM, Raemdonck K, Vader P (2013) Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release 172:229–238. https://doi.org/10.1016/j.jconrel.2013.08.014

    Article  CAS  PubMed  Google Scholar 

  25. Kanada M, Bachmann MH, Hardy JW, Frimannson DO, Bronsart L, Wang A, Sylvester MD, Schmidt TL, Kaspar RL, Butte MJ, Matin AC, Contag CH (2015) Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc Natl Acad Sci USA 112:E1433–E1442. https://doi.org/10.1073/pnas.1418401112

    Article  CAS  PubMed  Google Scholar 

  26. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, Strobel T, Breakefield XO, Saydam O (2013) Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther 21:101–108. https://doi.org/10.1038/mt.2012.161

    Article  CAS  PubMed  Google Scholar 

  27. Ohno SI, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M (2013) Systemically injected exosomes targeted to EGFR deliver antitumor MicroRNA to breast cancer cells. Mol Ther 21:185–191. https://doi.org/10.1038/mt.2012.180

    Article  CAS  PubMed  Google Scholar 

  28. Bellavia D, Raimondo S, Calabrese G, Forte S, Cristaldi M, Patinella A, Memeo L, Manno M, Raccosta S, Diana P, Cirrincione G, Giavaresi G, Monteleone F, Fontana S, De Leo G, Alessandro R (2017) Interleukin 3-receptor targeted exosomes inhibit in vitro and in vivo chronic myelogenous leukemia cell growth. Theranostics 7:1333–1345. https://doi.org/10.7150/thno.17092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalani A, Kamat PK, Chaturvedi P, Tyagi SC, Tyagi N (2014) Curcumin-primed exosomes mitigate endothelial cell dysfunction during hyperhomocysteinemia. Life Sci 107:1–7. https://doi.org/10.1016/j.lfs.2014.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wahlgren J, De LKT, Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, Valadi H (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40:e130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shtam TA, Kovalev RA, Varfolomeeva EY, Makarov EM, Kil YV, Filatov MV (2013) Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal 11:88. https://doi.org/10.1186/1478-811X-11-88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 3:22. https://doi.org/10.1002/0471143030.cb0322s30

    Article  PubMed  Google Scholar 

  33. Antimisiaris S, Mourtas S, Papadia K (2017) Targeted si-RNA with liposomes and exosomes (extracellular vesicles): how to unlock the potential. Int J Pharm 525:293–312. https://doi.org/10.1016/j.ijpharm.2017.01.056

    Article  CAS  PubMed  Google Scholar 

  34. Tomizawa M, Shinozaki F, Motoyoshi Y, Sugiyama T, Yamamoto S, Sueishi M (2013) Sonoporation: gene transfer using ultrasound. World J Methodol 3:39–44. https://doi.org/10.5662/wjm.v3.i4.39

    Article  PubMed  PubMed Central  Google Scholar 

  35. Agrawal AK, Aqil F, Jeyabalan J, Spencer WA, Beck J, Gachuki BW, Alhakeem SS, Oben K, Munagala R, Bondada S, Gupta RC (2017) Milk-derived exosomes for oral delivery of paclitaxel. Nanomed Nanotechnol Biol Med 13:1627–1636

    Article  CAS  Google Scholar 

  36. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, Batrakova EV (2015) Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Controll Release 207:18–30

    Article  CAS  Google Scholar 

  37. Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, Jiang X, Hou D, Chen X, Chen Y, Yang Z, Jin L, Jiang W, Tian C, Zhou G, Zen K, Zhang J, Zhang Y, Li J, Zhang CY (2015) Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep 5:17543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18:1606–1614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lamichhane TN, Jeyaram A, Patel DB, Parajuli B, Livingston NK, Arumugasaamy N, Schardt JS, Jay SM (2016) Oncogene knockdown via active loading of small RNAs into extracellular vesicles by sonication. Cell Mol Bioeng 9:315–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. O’Loughlin AJ, Mager I, de Jong OG, Varela MA, Schiffelers RM, El Andaloussi S, Wood MJA, Vader P (2017) Functional delivery of lipid-conjugated siRNA by extracellular vesicles. Mol Ther 25:1580–1587. https://doi.org/10.1016/j.ymthe.2017.03.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yim N, Choi C (2016) Extracellular vesicles as novel carriers for therapeutic molecules. BMB Rep 49:585–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yim N, Ryu SW, Choi K, Lee KR, Lee S, Choi H, Kim J, Shaker MR, Sun W, Park JH, Kim D, Heo WD, Choi C (2016) Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat Commun 7:12277. https://doi.org/10.1038/ncomms12277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institute of Health Grants: HL74185, HL139047 and AR71789.

Author information

Authors and Affiliations

  1. Department of Physiology, Health Sciences Centre A-1210, University of Louisville, School of Medicine, 500, South Preston Street, Louisville, KY, 40202, USA

    Anastasia Familtseva, Nevena Jeremic & Suresh C. Tyagi

Authors
  1. Anastasia Familtseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nevena Jeremic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh C. Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nevena Jeremic.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Familtseva, A., Jeremic, N. & Tyagi, S.C. Exosomes: cell-created drug delivery systems. Mol Cell Biochem 459, 1–6 (2019). https://doi.org/10.1007/s11010-019-03545-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-019-03545-4

Keywords

Search

Navigation