Prospects and challenges of exosomes as drug delivery systems_Journal of Biomedical Engineering

Authors：

MENG Wanrong ,  LI Ling , ZHU Guiquan

Sichuan Cancer Hospital& Institute, Sichuan Cancer Center, Sichuan Key Laboratory of Radiation Oncology School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, P.R. China;

Corresponding author：

Keywords：

drug delivery systems; extracellular vesicles; exosomes

DOI：

10.7507/1001-5515.201810027

Video：

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Abstract Full text Figures/Tables Video References Cited by

Exosomes are nanoscale vectors with a diameter of 30~100 nm secreted by living cells, and they are important media for intercellular communication. Recent studies have demonstrated that exosomes can not only serve as biomarkers for diagnosis, but also have great potential as natural drug delivery vectors. Exosomes can be loaded with therapeutic cargos, including small molecules, proteins, and oligonucleotides. Meanwhile, the unique biological compatibility, high stability, and tumor targeting of exosomes make them attractive in future tumor therapy. Though exosomes can effectively deliver bioactive materials to receptor cells, there is a wide gap between our current understanding of exosomes and their application as ideal drug delivery systems. In this review, we will briefly introduce the function and composition of exosomes, and mainly summarize the potential advantages and challenges of exosomes as drug carriers. Finally, this review is expected to provide new ideas for the development of exosome-based drug delivery systems.

Citation： MENG Wanrong, LI Ling, ZHU Guiquan. Prospects and challenges of exosomes as drug delivery systems. Journal of Biomedical Engineering, 2020, 37(4): 714-720. doi: 10.7507/1001-5515.201810027 Copy

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2.	Zhu Guiquan, Tang Yaling, Li Ling, <italic>et al</italic>. Abstract 1547: tumor-derived macrophage migration inhibitory factor and interleukin-6 cooperated in hypoxic accumulation of CD11b+Gr-1+ myeloid cells. Cancer Research, 2013, 73(8 suppl): 1547.
3.	Li Ling, Li Chao, Wang Shaoxin, <italic>et al</italic>. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res, 2016, 76(7): 1770-1780.
4.	Li L, Cao B, Liang X, <italic>et al</italic>. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene, 2019, 38(15): 2830-2843.
5.	Li L, Lu S, Liang X, <italic>et al</italic>. γδTDEs: an efficient delivery system for miR-138 with anti-tumoral and immunostimulatory roles on oral squamous cell carcinoma. Mol Ther Nucleic Acids, 2019, 14: 101-113.
6.	Piffoux M, Silva A K, Wilhelm C, <italic>et al</italic>. Modification of extracellular vesicles by fusion with liposomes for the design of personalized biogenic drug delivery systems. ACS Nano, 2018, 12(7): 6830-6842.
7.	Li Pin, Kaslan M, Lee S H, <italic>et al</italic>. Progress in exosome isolation techniques. Theranostics, 2017, 7(3): 789-804.
8.	Cesi G, Walbrecq G, Margue C, <italic>et al</italic>. Transferring intercellular signals and traits between cancer cells: extracellular vesicles as “homing pigeons”. Cell Commun Signal, 2016, 14(1): 13.
9.	Pitt J M, André F, Amigorena S, <italic>et al</italic>. Dendritic cell-derived exosomes for cancer therapy. J Clin Invest, 2016, 126(4): 1224-1232.
10.	Crewe C, Joffin N, Rutkowski J M, <italic>et al</italic>. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell, 2018, 175(3): 695-708.
11.	Namee N M, O'driscoll L. Extracellular vesicles and anti-cancer drug resistance. Biochimica et Biophysica Acta-Reviews on Cancer, 2018, 1870(2): 123-136.
12.	Tian H, Li Wei. Dendritic cell-derived exosomes for cancer immunotherapy: hope and challenges. Annals of translational medicine, 2017, 5(10): 221.
13.	Chen Shisheng, Lv Mingfen, Fang Shan, <italic>et al</italic>. Poly(I: C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes. Int J Biol Macromol, 2018, 113: 1182-1187.
14.	Mendt M, Kamerkar S, Sugimoto H, <italic>et al</italic>. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI insight, 2018, 3(8): 99263.
15.	Zhu L, Oh J M, Gangadaran P, <italic>et al</italic>. Targeting and therapy of glioblastoma in a mouse model using exosomes derived from natural killer cells. Front Immunol, 2018, 9: 824.
16.	Guo M, Wu F, Hu Guorong, <italic>et al</italic>. Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion. Sci Transl Med, 2019, 11(474): eaat5690.
17.	Aqil F, Munagala R, Jeyabalan J, <italic>et al</italic>. Milk exosomes-natural nanoparticles for siRNA delivery. Cancer Lett, 2019, 449: 186-195.
18.	Shi M, Sheng Lifu, Stewart T, <italic>et al</italic>. New Windows into the brain: central nervous system-derived extracellular vesicles in blood. Prog Neurobiol, 2019, 175: 96-106.
19.	Jung K O, Jo H, Yu J H, <italic>et al</italic>. Development and MPI tracking of novel hypoxia-targeted theranostic exosomes. Biomaterials, 2018, 177: 139-148.
20.	Alvarez-Erviti L, Seow Y, Yin Haifang, <italic>et al</italic>. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol, 2011, 29(4): 341-345.
21.	Cheng Q, Shi Xiaojing, Han Menglu, <italic>et al</italic>. Reprogramming exosomes as nanoscale controllers of cellular immunity. J Am Chem Soc, 2018, 140(48): 16413-16417.
22.	Limoni S K, Moghadam M F, Moazzeni S M, <italic>et al</italic>. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Appl Biochem Biotechnol, 2019, 187(1): 352-364.
23.	Piffoux M, Nicolás-Boluda A, Mulens-Arias V, <italic>et al</italic>. Extracellular vesicles for personalized medicine: the input of physically triggered production, loading and theranostic properties. Adv Drug Deliv Rev, 2019, 138: 247-258.
24.	Whitford W, Ludlow J W, Cadwell J S. Continuous production of exosomes. Genetic Engineering & Biotechnology News, 2015, 35(16): 34.
25.	Watson D C, Bayik D, Srivatsan A, <italic>et al</italic>. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials, 2016, 105: 195-205.
26.	Sun Li, Wang Hongxiang, Zhu Xiaojian, <italic>et al</italic>. Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells <italic>in vitro</italic>. Acta Pharmacol Sin, 2014, 35(3): 381-393.
27.	Wysoczynski M, Ratajczak M Z. Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. International Journal of Cancer, 2009, 125(7): 1595-1603.
28.	King H W, Michael M Z, Gleadle J M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 2012, 12(1): 421.
29.	Headland S E, Jones H R, D'sa A S, <italic>et al</italic>. Cutting-edge analysis of extracellular microparticles using ImageStream(X) imaging flow cytometry. Sci Rep, 2014, 4(1): 5237.
30.	Pick H, Schmid E L, Tairi A P, <italic>et al</italic>. Investigating cellular signaling reactions in single attoliter vesicles. J Am Chem Soc, 2005, 127(9): 2908-2912.
31.	Mao Z, Cartier R, Hohl A, <italic>et al</italic>. Cells as factories for humanized encapsulation. Nano Lett, 2011, 11(5): 2152-2156.
32.	Momen-Heravi F, Bala Shashi, Kodys K, <italic>et al</italic>. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep, 2015, 5(1): 9991.
33.	Jo W, Jeong D, Kim J, <italic>et al</italic>. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. Lab Chip, 2014, 14(7): 1261-1269.
34.	Piffoux M, Silva A K, Lugagne J B, <italic>et al</italic>. Extracellular vesicle production loaded with nanoparticles and drugs in a trade-off between loading, yield and purity: towards a personalized drug delivery system. Advanced biosystems, 2017, 1(5): e1700044.
35.	Batrakova E V, Kim M S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 2015, 219: 396-405.
36.	Lee J, Kim J, Jeong M, <italic>et al</italic>. Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. Nano Lett, 2015, 15(5): 2938-2944.
37.	Sun Dongmei, Zhuang Xiaoying, Xiang Xiaoyu, <italic>et al</italic>. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy, 2010, 18(9): 1606-1614.
38.	Tian Yanhua, Li Suping, Song Jian, <italic>et al</italic>. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials, 2014, 35(7): 2383-2390.
39.	Kim M S, Haney M J, Zhao Yuling, <italic>et al</italic>. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine: Nanotechnology, Biology and Medicine, 2016, 12(3): 655-664.
40.	Haney M J, Klyachko N L, Zhao Yuling, <italic>et al</italic>. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release, 2015, 207: 18-30.
41.	Li Z, Zhou Xueying, Wei Mengying, <italic>et al</italic>. <italic>In vitro</italic> and <italic>in vivo</italic> RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. Nano Lett, 2019, 19(1): 19-28.
42.	Kanchanapally R, Deshmukh S K, Chavva S R, <italic>et al</italic>. Drug-loaded exosomal preparations from different cell types exhibit distinctive loading capability, yield, and antitumor efficacies: a comparative analysis. Int J Nanomedicine, 2019, 14: 531-541.
43.	Zhuang X, Xiang X, Grizzle W, <italic>et al</italic>. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther, 2011, 19(10): 1769-1779.
44.	Agrawal A K, Aqil F, Jeyabalan J, <italic>et al</italic>. Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine: Nanotechnology, Biology and Medicine, 2017, 13(5): 1627-1636.
45.	Hong Y, Nam G, Koh E, <italic>et al</italic>. Exosome as a vehicle for delivery of membrane protein therapeutics, PH20, for enhanced tumor penetration and antitumor efficacy. Adv Funct Mater, 2018, 28(17): 1801301.
46.	Bellavia D, Raimondo S, Calabrese G A, <italic>et al</italic>. Interleukin 3-receptor targeted exosomes inhibit <italic>in vitro</italic> and <italic>in vivo</italic> chronic myelogenous leukemia cell growth. Theranostics, 2017, 7(5): 1333-1345.
47.	Momen-Heravi F, Bala S, Bukong T, <italic>et al</italic>. Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine: Nanotechnology, Biology and Medicine, 2014, 10(7): 1517-1527.
48.	Darband S G, Mirza-aghazadeh-attari M, Kaviani M, <italic>et al</italic>. Exosomes: natural nanoparticles as bio shuttles for RNAi delivery. J Control Release, 2018, 289: 158-170.
49.	Bose R J, Kumar S U, Zeng Y, <italic>et al</italic>. Tumor cell-derived extracellular vesicle-coated nanocarriers: an efficient theranostic platform for the cancer-specific delivery of anti-miR-21 and imaging agents. ACS Nano, 2018, 12(11): 10817-10832.
50.	Yang B, Chen Yu, Shi J. Exosome biochemistry and advanced nanotechnology for next-generation theranostic platforms. Adv Mater, 2019, 31(2): e1802896.
51.	Kamerkar S, Lebleu V S, Sugimoto H, <italic>et al</italic>. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
52.	Usman W M, Pham T C, Kwok Y Y, <italic>et al</italic>. Efficient RNA drug delivery using red blood cell extracellular vesicles. Nat Commun, 2018, 9(1): 2359.
53.	Armstrong J P, Holme M N, Stevens M M. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano, 2017, 11(1): 69-83.
54.	Yang Y, Tai Xiaowei, Shi Kairong, <italic>et al</italic>. A new concept of enhancing immuno-chemotherapeutic effects against B16F10 tumor via systemic administration by taking advantages of the limitation of EPR effect. Theranostics, 2016, 6(12): 2141-2160.
55.	Kooijmans S, Fliervoet L A L, van der Meel R, <italic>et al</italic>. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release, 2016, 224: 77-85.
56.	Shen Wen, Guo Kaizhu, Adkins G B, <italic>et al</italic>. A single extracellular vesicle (EV) flow cytometry approach to reveal EV heterogeneity. Angew Chem Int Ed Engl, 2018, 57(48): 15675-15680.

1. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol, 2002, 2(8): 569-579.
2. Zhu Guiquan, Tang Yaling, Li Ling, <italic>et al</italic>. Abstract 1547: tumor-derived macrophage migration inhibitory factor and interleukin-6 cooperated in hypoxic accumulation of CD11b+Gr-1+ myeloid cells. Cancer Research, 2013, 73(8 suppl): 1547.
3. Li Ling, Li Chao, Wang Shaoxin, <italic>et al</italic>. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res, 2016, 76(7): 1770-1780.
4. Li L, Cao B, Liang X, <italic>et al</italic>. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene, 2019, 38(15): 2830-2843.
5. Li L, Lu S, Liang X, <italic>et al</italic>. γδTDEs: an efficient delivery system for miR-138 with anti-tumoral and immunostimulatory roles on oral squamous cell carcinoma. Mol Ther Nucleic Acids, 2019, 14: 101-113.
6. Piffoux M, Silva A K, Wilhelm C, <italic>et al</italic>. Modification of extracellular vesicles by fusion with liposomes for the design of personalized biogenic drug delivery systems. ACS Nano, 2018, 12(7): 6830-6842.
7. Li Pin, Kaslan M, Lee S H, <italic>et al</italic>. Progress in exosome isolation techniques. Theranostics, 2017, 7(3): 789-804.
8. Cesi G, Walbrecq G, Margue C, <italic>et al</italic>. Transferring intercellular signals and traits between cancer cells: extracellular vesicles as “homing pigeons”. Cell Commun Signal, 2016, 14(1): 13.
9. Pitt J M, André F, Amigorena S, <italic>et al</italic>. Dendritic cell-derived exosomes for cancer therapy. J Clin Invest, 2016, 126(4): 1224-1232.
10. Crewe C, Joffin N, Rutkowski J M, <italic>et al</italic>. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell, 2018, 175(3): 695-708.
11. Namee N M, O'driscoll L. Extracellular vesicles and anti-cancer drug resistance. Biochimica et Biophysica Acta-Reviews on Cancer, 2018, 1870(2): 123-136.
12. Tian H, Li Wei. Dendritic cell-derived exosomes for cancer immunotherapy: hope and challenges. Annals of translational medicine, 2017, 5(10): 221.
13. Chen Shisheng, Lv Mingfen, Fang Shan, <italic>et al</italic>. Poly(I: C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes. Int J Biol Macromol, 2018, 113: 1182-1187.
14. Mendt M, Kamerkar S, Sugimoto H, <italic>et al</italic>. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI insight, 2018, 3(8): 99263.
15. Zhu L, Oh J M, Gangadaran P, <italic>et al</italic>. Targeting and therapy of glioblastoma in a mouse model using exosomes derived from natural killer cells. Front Immunol, 2018, 9: 824.
16. Guo M, Wu F, Hu Guorong, <italic>et al</italic>. Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion. Sci Transl Med, 2019, 11(474): eaat5690.
17. Aqil F, Munagala R, Jeyabalan J, <italic>et al</italic>. Milk exosomes-natural nanoparticles for siRNA delivery. Cancer Lett, 2019, 449: 186-195.
18. Shi M, Sheng Lifu, Stewart T, <italic>et al</italic>. New Windows into the brain: central nervous system-derived extracellular vesicles in blood. Prog Neurobiol, 2019, 175: 96-106.
19. Jung K O, Jo H, Yu J H, <italic>et al</italic>. Development and MPI tracking of novel hypoxia-targeted theranostic exosomes. Biomaterials, 2018, 177: 139-148.
20. Alvarez-Erviti L, Seow Y, Yin Haifang, <italic>et al</italic>. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol, 2011, 29(4): 341-345.
21. Cheng Q, Shi Xiaojing, Han Menglu, <italic>et al</italic>. Reprogramming exosomes as nanoscale controllers of cellular immunity. J Am Chem Soc, 2018, 140(48): 16413-16417.
22. Limoni S K, Moghadam M F, Moazzeni S M, <italic>et al</italic>. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Appl Biochem Biotechnol, 2019, 187(1): 352-364.
23. Piffoux M, Nicolás-Boluda A, Mulens-Arias V, <italic>et al</italic>. Extracellular vesicles for personalized medicine: the input of physically triggered production, loading and theranostic properties. Adv Drug Deliv Rev, 2019, 138: 247-258.
24. Whitford W, Ludlow J W, Cadwell J S. Continuous production of exosomes. Genetic Engineering & Biotechnology News, 2015, 35(16): 34.
25. Watson D C, Bayik D, Srivatsan A, <italic>et al</italic>. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials, 2016, 105: 195-205.
26. Sun Li, Wang Hongxiang, Zhu Xiaojian, <italic>et al</italic>. Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells <italic>in vitro</italic>. Acta Pharmacol Sin, 2014, 35(3): 381-393.
27. Wysoczynski M, Ratajczak M Z. Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. International Journal of Cancer, 2009, 125(7): 1595-1603.
28. King H W, Michael M Z, Gleadle J M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 2012, 12(1): 421.
29. Headland S E, Jones H R, D'sa A S, <italic>et al</italic>. Cutting-edge analysis of extracellular microparticles using ImageStream(X) imaging flow cytometry. Sci Rep, 2014, 4(1): 5237.
30. Pick H, Schmid E L, Tairi A P, <italic>et al</italic>. Investigating cellular signaling reactions in single attoliter vesicles. J Am Chem Soc, 2005, 127(9): 2908-2912.
31. Mao Z, Cartier R, Hohl A, <italic>et al</italic>. Cells as factories for humanized encapsulation. Nano Lett, 2011, 11(5): 2152-2156.
32. Momen-Heravi F, Bala Shashi, Kodys K, <italic>et al</italic>. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep, 2015, 5(1): 9991.
33. Jo W, Jeong D, Kim J, <italic>et al</italic>. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. Lab Chip, 2014, 14(7): 1261-1269.
34. Piffoux M, Silva A K, Lugagne J B, <italic>et al</italic>. Extracellular vesicle production loaded with nanoparticles and drugs in a trade-off between loading, yield and purity: towards a personalized drug delivery system. Advanced biosystems, 2017, 1(5): e1700044.
35. Batrakova E V, Kim M S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 2015, 219: 396-405.
36. Lee J, Kim J, Jeong M, <italic>et al</italic>. Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. Nano Lett, 2015, 15(5): 2938-2944.
37. Sun Dongmei, Zhuang Xiaoying, Xiang Xiaoyu, <italic>et al</italic>. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy, 2010, 18(9): 1606-1614.
38. Tian Yanhua, Li Suping, Song Jian, <italic>et al</italic>. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials, 2014, 35(7): 2383-2390.
39. Kim M S, Haney M J, Zhao Yuling, <italic>et al</italic>. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine: Nanotechnology, Biology and Medicine, 2016, 12(3): 655-664.
40. Haney M J, Klyachko N L, Zhao Yuling, <italic>et al</italic>. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release, 2015, 207: 18-30.
41. Li Z, Zhou Xueying, Wei Mengying, <italic>et al</italic>. <italic>In vitro</italic> and <italic>in vivo</italic> RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. Nano Lett, 2019, 19(1): 19-28.
42. Kanchanapally R, Deshmukh S K, Chavva S R, <italic>et al</italic>. Drug-loaded exosomal preparations from different cell types exhibit distinctive loading capability, yield, and antitumor efficacies: a comparative analysis. Int J Nanomedicine, 2019, 14: 531-541.
43. Zhuang X, Xiang X, Grizzle W, <italic>et al</italic>. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther, 2011, 19(10): 1769-1779.
44. Agrawal A K, Aqil F, Jeyabalan J, <italic>et al</italic>. Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine: Nanotechnology, Biology and Medicine, 2017, 13(5): 1627-1636.
45. Hong Y, Nam G, Koh E, <italic>et al</italic>. Exosome as a vehicle for delivery of membrane protein therapeutics, PH20, for enhanced tumor penetration and antitumor efficacy. Adv Funct Mater, 2018, 28(17): 1801301.
46. Bellavia D, Raimondo S, Calabrese G A, <italic>et al</italic>. Interleukin 3-receptor targeted exosomes inhibit <italic>in vitro</italic> and <italic>in vivo</italic> chronic myelogenous leukemia cell growth. Theranostics, 2017, 7(5): 1333-1345.
47. Momen-Heravi F, Bala S, Bukong T, <italic>et al</italic>. Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine: Nanotechnology, Biology and Medicine, 2014, 10(7): 1517-1527.
48. Darband S G, Mirza-aghazadeh-attari M, Kaviani M, <italic>et al</italic>. Exosomes: natural nanoparticles as bio shuttles for RNAi delivery. J Control Release, 2018, 289: 158-170.
49. Bose R J, Kumar S U, Zeng Y, <italic>et al</italic>. Tumor cell-derived extracellular vesicle-coated nanocarriers: an efficient theranostic platform for the cancer-specific delivery of anti-miR-21 and imaging agents. ACS Nano, 2018, 12(11): 10817-10832.
50. Yang B, Chen Yu, Shi J. Exosome biochemistry and advanced nanotechnology for next-generation theranostic platforms. Adv Mater, 2019, 31(2): e1802896.
51. Kamerkar S, Lebleu V S, Sugimoto H, <italic>et al</italic>. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
52. Usman W M, Pham T C, Kwok Y Y, <italic>et al</italic>. Efficient RNA drug delivery using red blood cell extracellular vesicles. Nat Commun, 2018, 9(1): 2359.
53. Armstrong J P, Holme M N, Stevens M M. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano, 2017, 11(1): 69-83.
54. Yang Y, Tai Xiaowei, Shi Kairong, <italic>et al</italic>. A new concept of enhancing immuno-chemotherapeutic effects against B16F10 tumor via systemic administration by taking advantages of the limitation of EPR effect. Theranostics, 2016, 6(12): 2141-2160.
55. Kooijmans S, Fliervoet L A L, van der Meel R, <italic>et al</italic>. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release, 2016, 224: 77-85.
56. Shen Wen, Guo Kaizhu, Adkins G B, <italic>et al</italic>. A single extracellular vesicle (EV) flow cytometry approach to reveal EV heterogeneity. Angew Chem Int Ed Engl, 2018, 57(48): 15675-15680.

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