Skip to content
2000
image of Precision Medicine: Design of Immune Inert Exosomes for Targeted Gene Delivery

Abstract

Exosomes represent the smallest size among extracellular vesicles, which also include apoptotic bodies and microvesicles. Exosomes are natural nanocarriers that play a key role in intracellular communication, consisting of a hydrophobic lipid bilayer membrane and a hydrophilic core. The membrane compositions of exosomes are similar to those of the parent cells from which they are generated. Normally, the exosome membrane contains diacylglycerol, ceramide, cholesterol, and various surface proteins, including tetraspanins and Lamb2. Almost all cell types secrete exosomes into body fluids through exocytosis, including stem cells, epithelial cells, endothelial cells, immune cells, tumor cells, neurons, mast cells, oligodendrocytes, reticulocytes, macrophages, platelets, and astrocytes. Every cell type expresses a distinct type of exosomes carrying various bioactive molecules. Exosomes are major transporters of bioactive cargo, including enzymes, receptors, growth and transcription factors, nucleic acids, lipids, and other metabolites, which strongly affect the physiology of recipient cells. Exosomes are not only potent drug and gene delivery nanocarriers, but also have potential for disease diagnosis, tissue regeneration, and immunomodulation. Exosomes are present in various body fluids, including plasma, serum, saliva, milk, nasal secretions, urine, amniotic fluid, semen, and cerebrospinal fluid, among others. Stem cell-made exosomes are potential natural therapeutics, which is due to their rejuvenating cargo and ability to cross biological barriers. However, natural exosomes' inefficient cargo transfer and short lifespan in the bloodstream have hindered their progress in therapeutic interventions. Genetic engineering of the parent cell allows for loading specific therapeutic cargo into the lumen of newly generated exosomes and/or displaying certain homing peptides or ligands at their surface, leading to extension of their lifespan and precise delivery to specific organs or tissues. This minireview explores the creation of designer exosomes through parent cell engineering and their utilization for guiding the delivery of tailored therapeutic cargo to specific organs while evading the host innate immune response.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cgt/10.2174/0115665232409032250908114520
2025-09-30
2025-10-29

  • From This Site

    /content/journals/cgt/10.2174/0115665232409032250908114520
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Gemel J. Kilkus J. Dawson G. Beyer E.C. Connecting exosomes and connexins. Cancers 2019 11 4 476 10.3390/cancers11040476 30987321
    [Google Scholar]
  2. Valadi H. Ekström K. Bossios A. Sjöstrand M. Lee J.J. Lötvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007 9 6 654 659 10.1038/ncb1596 17486113
    [Google Scholar]
  3. Balaj L. Lessard R. Dai L. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2011 2 1 180 10.1038/ncomms1180 21285958
    [Google Scholar]
  4. Kalluri R. LeBleu V.S. The biology, function, and biomedical applications of exosomes. Science 2020 367 6478 eaau6977 10.1126/science.aau6977 32029601
    [Google Scholar]
  5. Chen Y.F. Luh F. Ho Y.S. Yen Y. Exosomes: A review of biologic function, diagnostic and targeted therapy applications, and clinical trials. J. Biomed. Sci. 2024 31 1 67 10.1186/s12929‑024‑01055‑0 38992695
    [Google Scholar]
  6. Zhuang X. Xiang X. Grizzle W. 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 10.1038/mt.2011.164 21915101
    [Google Scholar]
  7. Sterzenbach U. Putz U. Low L.H. Silke J. Tan S.S. Howitt J. Engineered exosomes as vehicles for biologically active proteins. Mol. Ther. 2017 25 6 1269 1278 10.1016/j.ymthe.2017.03.030 28412169
    [Google Scholar]
  8. Li Q. Fu X. Kou Y. Han N. Engineering strategies and optimized delivery of exosomes for theranostic application in nerve tissue. Theranostics 2023 13 12 4266 4286 10.7150/thno.84971 37554270
    [Google Scholar]
  9. Herrmann I.K. Wood M.J.A. Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat. Nanotechnol. 2021 16 7 748 759 10.1038/s41565‑021‑00931‑2 34211166
    [Google Scholar]
  10. Klyachko N.L. Arzt C.J. Li S.M. Gololobova O.A. Batrakova E.V. Extracellular vesicle-based therapeutics: Preclinical and clinical investigations. Pharmaceutics 2020 12 12 1171 10.3390/pharmaceutics12121171 33271883
    [Google Scholar]
  11. Yang T. Martin P. Fogarty B. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm. Res. 2015 32 6 2003 2014 10.1007/s11095‑014‑1593‑y 25609010
    [Google Scholar]
  12. Imai T. Takahashi Y. Nishikawa M. Macrophage‐dependent clearance of systemically administered B16BL6‐derived exosomes from the blood circulation in mice. J. Extracell. Vesicles 2015 4 1 26238 10.3402/jev.v4.26238 25669322
    [Google Scholar]
  13. Choi H. Kim Y. Mirzaaghasi A. Exosome-based delivery of super-repressor IκBα relieves sepsis-associated organ damage and mortality. Sci. Adv. 2020 6 15 eaaz6980 10.1126/sciadv.aaz6980 32285005
    [Google Scholar]
  14. Choi H. Choi Y. Yim H.Y. Mirzaaghasi A. Yoo J.K. Choi C. Biodistribution of exosomes and engineering strategies for targeted delivery of therapeutic exosomes. Tissue Eng. Regen. Med. 2021 18 4 499 511 10.1007/s13770‑021‑00361‑0 34260047
    [Google Scholar]
  15. Smyth T. Kullberg M. Malik N. Smith-Jones P. Graner M.W. Anchordoquy T.J. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release 2015 199 145 155 10.1016/j.jconrel.2014.12.013 25523519
    [Google Scholar]
  16. Wiklander O.P.B. Nordin J.Z. O’Loughlin A. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 2015 4 1 26316 10.3402/jev.v4.26316 25899407
    [Google Scholar]
  17. Faruqu F.N. Wang J.T.W. Xu L. Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice - A novel and universal approach. Theranostics 2019 9 6 1666 1682 10.7150/thno.27891 31037130
    [Google Scholar]
  18. Grange C. Tapparo M. Bruno S. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int. J. Mol. Med. 2014 33 5 1055 1063 10.3892/ijmm.2014.1663 24573178
    [Google Scholar]
  19. Harding C. Stahl P. Transferrin recycling in reticulocytes: PH and iron are important determinants of ligand binding and processing. Biochem. Biophys. Res. Commun. 1983 113 2 650 658 10.1016/0006‑291X(83)91776‑X 6870878
    [Google Scholar]
  20. Pan B.T. Johnstone R.M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell 1983 33 3 967 978 10.1016/0092‑8674(83)90040‑5 6307529
    [Google Scholar]
  21. Zhang Y. Liu Y. Liu H. Tang W.H. Exosomes: Biogenesis, biologic function and clinical potential. Cell Biosci. 2019 9 1 19 10.1186/s13578‑019‑0282‑2 30815248
    [Google Scholar]
  22. Agarwal S. Agarwal V. Agarwal M. Singh M. Exosomes: Structure, biogenesis, types and application in diagnosis and gene and drug delivery. Curr. Gene Ther. 2020 20 3 195 206 10.2174/1566523220999200731011702 32787759
    [Google Scholar]
  23. Jia X. Yin Y. Chen Y. Mao L. The role of viral proteins in the regulation of exosomes biogenesis. Front. Cell. Infect. Microbiol. 2021 11 671625 10.3389/fcimb.2021.671625 34055668
    [Google Scholar]
  24. Dyball L.E. Smales C.M. Exosomes: Biogenesis, targeting, characterization and their potential as “Plug & Play” vaccine platforms. Biotechnol. J. 2022 17 11 2100646 10.1002/biot.202100646 35899790
    [Google Scholar]
  25. Krylova S.V. Feng D. The machinery of exosomes: Biogenesis, release, and uptake. Int. J. Mol. Sci. 2023 24 2 1337 10.3390/ijms24021337 36674857
    [Google Scholar]
  26. Bahadorani M. Nasiri M. Dellinger K. Aravamudhan S. Zadegan R. Engineering exosomes for therapeutic applications: Decoding biogenesis, content modification, and cargo loading strategies. Int. J. Nanomedicine 2024 19 7137 7164 10.2147/IJN.S464249 39050874
    [Google Scholar]
  27. Yuan Y.G. Wang J.L. Zhang Y.X. Li L. Reza A.M.M.T. Gurunathan S. Biogenesis, composition and potential therapeutic applications of mesenchymal stem cells derived exosomes in various diseases. Int. J. Nanomedicine 2023 18 3177 3210 10.2147/IJN.S407029 37337578
    [Google Scholar]
  28. Datta A. Kim H. McGee L. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer. Sci. Rep. 2018 8 1 8161 10.1038/s41598‑018‑26411‑7 29802284
    [Google Scholar]
  29. Greenberg J.W. Kim H. Ahn M. Combination of tipifarnib and sunitinib overcomes renal cell carcinoma resistance to tyrosine kinase inhibitors via tumor-derived exosome and T cell modulation. Cancers 2022 14 4 903 10.3390/cancers14040903 35205655
    [Google Scholar]
  30. Johansson L. Reyes J.F. Ali T. Schätzl H. Gilch S. Hallbeck M. Lack of cellular prion protein causes Amyloid β accumulation, increased extracellular vesicle abundance, and changes to exosome biogenesis proteins. Mol. Cell. Biochem. 2025 480 3 1569 1582 10.1007/s11010‑024‑05059‑0 38970706
    [Google Scholar]
  31. Choudhery M.S. Arif T. Mahmood R. Harris D.T. Stem cell-based acellular therapy: Insight into biogenesis, bioengineering and therapeutic applications of exosomes. Biomolecules 2024 14 7 792 10.3390/biom14070792 39062506
    [Google Scholar]
  32. Xiao X. Yu S. Li S. Exosomes: Decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One 2014 9 2 e89534 10.1371/journal.pone.0089534 24586853
    [Google Scholar]
  33. Man K. Brunet M.Y. Jones M.C. Cox S.C. Engineered extracellular vesicles: Tailored-made nanomaterials for medical applications. Nanomaterials 2020 10 9 1838 10.3390/nano10091838 32942556
    [Google Scholar]
  34. King H.W. Michael M.Z. Gleadle J.M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012 12 1 421 10.1186/1471‑2407‑12‑421 22998595
    [Google Scholar]
  35. Kanemoto S. Nitani R. Murakami T. Multivesicular body formation enhancement and exosome release during endoplasmic reticulum stress. Biochem. Biophys. Res. Commun. 2016 480 2 166 172 10.1016/j.bbrc.2016.10.019 27725157
    [Google Scholar]
  36. Pericoli G. Galardi A. Paolini A. Inhibition of exosome biogenesis affects cell motility in heterogeneous sub-populations of paediatric-type diffuse high-grade gliomas. Cell Biosci. 2023 13 1 207 10.1186/s13578‑023‑01166‑5 37957701
    [Google Scholar]
  37. Khan H. Pan J.J. Li Y. Zhang Z. Yang G.Y. Native and bioengineered exosomes for ischemic stroke therapy. Front. Cell Dev. Biol. 2021 9 619565 10.3389/fcell.2021.619565 33869170
    [Google Scholar]
  38. Parada N. Romero-Trujillo A. Georges N. Alcayaga-Miranda F. Camouflage strategies for therapeutic exosomes evasion from phagocytosis. J. Adv. Res. 2021 31 61 74 10.1016/j.jare.2021.01.001 34194832
    [Google Scholar]
  39. Chen S. Sun F. Qian H. Xu W. Jiang J. Preconditioning and engineering strategies for improving the efficacy of mesenchymal stem cell-derived exosomes in cell-free therapy. Stem Cells Int. 2022 2022 1 18 10.1155/2022/1779346 35607400
    [Google Scholar]
  40. Huang L. Wu E. Liao J. Wei Z. Wang J. Chen Z. Research advances of engineered exosomes as drug delivery carrier. ACS Omega 2023 8 46 43374 43387 10.1021/acsomega.3c04479 38027310
    [Google Scholar]
  41. Mondal J. Pillarisetti S. Junnuthula V. Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications. J. Control. Release 2023 353 1127 1149 10.1016/j.jconrel.2022.12.027 36528193
    [Google Scholar]
  42. Palicharla V.R. Maddika S. HACE1 mediated K27 ubiquitin linkage leads to YB-1 protein secretion. Cell. Signal. 2015 27 12 2355 2362 10.1016/j.cellsig.2015.09.001 26343856
    [Google Scholar]
  43. Wei J. Lv L. Wan Y. Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology 2015 61 4 1284 1294 10.1002/hep.27660 25503676
    [Google Scholar]
  44. Géminard C. de Gassart A. Blanc L. Vidal M. Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TFR for sorting into exosomes. Traffic 2004 5 3 181 193 10.1111/j.1600‑0854.2004.0167.x 15086793
    [Google Scholar]
  45. Iavello A. Frech V.S.L. Gai C. Deregibus M.C. Quesenberry P.J. Camussi G. Role of Alix in miRNA packaging during extracellular vesicle biogenesis. Int. J. Mol. Med. 2016 37 4 958 966 10.3892/ijmm.2016.2488 26935291
    [Google Scholar]
  46. Haney M.J. Klyachko N.L. Zhao Y. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release 2015 207 18 30 10.1016/j.jconrel.2015.03.033 25836593
    [Google Scholar]
  47. Piffoux M. Volatron J. Cherukula K. Engineering and loading therapeutic extracellular vesicles for clinical translation: A data reporting frame for comparability. Adv. Drug Deliv. Rev. 2021 178 113972 10.1016/j.addr.2021.113972 34509573
    [Google Scholar]
  48. Cheng J. Sun Y. Ma Y. Ao Y. Hu X. Meng Q. Engineering of MSC-derived exosomes: A promising cell-free therapy for osteoarthritis. Membranes 2022 12 8 739 10.3390/membranes12080739 36005656
    [Google Scholar]
  49. Ahmed W. Mushtaq A. Ali S. Khan N. Liang Y. Duan L. Engineering approaches for exosome cargo loading and targeted delivery: Biological versus chemical perspectives. ACS Biomater. Sci. Eng. 2024 10 10 5960 5976 10.1021/acsbiomaterials.4c00856 38940421
    [Google Scholar]
  50. Harvey K.F. Shearwin-Whyatt L.M. Fotia A. Parton R.G. Kumar S. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J. Biol. Chem. 2002 277 11 9307 9317 10.1074/jbc.M110443200 11748237
    [Google Scholar]
  51. Sang Q. Kim M.H. Kumar S. Nedd4-WW domain-binding protein 5 (Ndfip1) is associated with neuronal survival after acute cortical brain injury. J. Neurosci. 2006 26 27 7234 7244 10.1523/JNEUROSCI.1398‑06.2006 16822981
    [Google Scholar]
  52. Putz U. Howitt J. Lackovic J. Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins. J. Biol. Chem. 2008 283 47 32621 32627 10.1074/jbc.M804120200 18819914
    [Google Scholar]
  53. Mund T. Pelham H.R.B. Control of the activity of WW‐HECT domain E3 ubiquitin ligases by NDFIP proteins. EMBO Rep. 2009 10 5 501 507 10.1038/embor.2009.30 19343052
    [Google Scholar]
  54. Staub O. Rotin D. WW domains. Structure 1996 4 5 495 499 10.1016/S0969‑2126(96)00054‑8 8736547
    [Google Scholar]
  55. Krämer-Albers E.M. Ticket to ride: Targeting proteins to exosomes for brain delivery. Mol. Ther. 2017 25 6 1264 1266 10.1016/j.ymthe.2017.05.001 28499750
    [Google Scholar]
  56. Hershko A. Ciechanover A. The ubiquitin system. Annu. Rev. Biochem. 1998 67 1 425 479 10.1146/annurev.biochem.67.1.425 9759494
    [Google Scholar]
  57. Mukhopadhyay D. Riezman H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 2007 315 5809 201 205 10.1126/science.1127085 17218518
    [Google Scholar]
  58. Kimura Y. Tanaka K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J. Biochem. 2010 147 6 793 798 10.1093/jb/mvq044 20418328
    [Google Scholar]
  59. Cheng Y. Schorey J.S. Targeting soluble proteins to exosomes using a ubiquitin tag. Biotechnol. Bioeng. 2016 113 6 1315 1324 10.1002/bit.25884 26574179
    [Google Scholar]
  60. Lu X. Yu H. Liu S.H. Brodsky F.M. Peterlin B.M. Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. Immunity 1998 8 5 647 656 10.1016/S1074‑7613(00)80569‑5 9620685
    [Google Scholar]
  61. de Gassart A. Géminard C. Février B. Raposo G. Vidal M. Lipid raft-associated protein sorting in exosomes. Blood 2003 102 13 4336 4344 10.1182/blood‑2003‑03‑0871 12881314
    [Google Scholar]
  62. Manfredi F. Di Bonito P. Arenaccio C. Anticoli S. Federico M. Incorporation of heterologous proteins in engineered exosomes. Methods Mol. Biol. 2016 1448 249 260 10.1007/978‑1‑4939‑3753‑0_18 27317186
    [Google Scholar]
  63. McNamara R.P. Costantini L.M. Myers T.A. Nef secretion into extracellular vesicles or exosomes is conserved across human and simian immunodeficiency viruses. MBio 2018 9 1 e02344 e17 10.1128/mBio.02344‑17 29437924
    [Google Scholar]
  64. Anticoli S. Manfredi F. Chiozzini C. An exosome‐based vaccine platform imparts cytotoxic T lymphocyte immunity against viral antigens. Biotechnol. J. 2018 13 4 1700443 10.1002/biot.201700443 29274250
    [Google Scholar]
  65. Yim N. Ryu S.W. Choi K. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module. Nat. Commun. 2016 7 1 12277 10.1038/ncomms12277 27447450
    [Google Scholar]
  66. Kennedy M.J. Hughes R.M. Peteya L.A. Schwartz J.W. Ehlers M.D. Tucker C.L. Rapid blue-light–mediated induction of protein interactions in living cells. Nat. Methods 2010 7 12 973 975 10.1038/nmeth.1524 21037589
    [Google Scholar]
  67. Liu H. Yu X. Li K. Photoexcited CRY2 interacts with CIB1 to regulate transcription and floral initiation in Arabidopsis. Science 2008 322 5907 1535 1539 10.1126/science.1163927 18988809
    [Google Scholar]
  68. Yazawa M. Sadaghiani A.M. Hsueh B. Dolmetsch R.E. Induction of protein-protein interactions in live cells using light. Nat. Biotechnol. 2009 27 10 941 945 10.1038/nbt.1569 19801976
    [Google Scholar]
  69. Batagov AO Kuznetsov VA Kurochkin IV Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles. BMC Genomics 2011 12 (Suppl 3) S18.(Suppl. 3) 10.1186/1471‑2164‑12‑S3‑S18 2236958
    [Google Scholar]
  70. Batagov A.O. Kurochkin I.V. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3′-untranslated regions. Biol. Direct 2013 8 1 12 10.1186/1745‑6150‑8‑12 23758897
    [Google Scholar]
  71. Garcia-Martin R. Wang G. Brandão B.B. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 2022 601 7893 446 451 10.1038/s41586‑021‑04234‑3 34937935
    [Google Scholar]
  72. Mittelbrunn M. Gutiérrez-Vázquez C. Villarroya-Beltri C. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2011 2 1 282 10.1038/ncomms1285 21505438
    [Google Scholar]
  73. Stoorvogel W. Functional transfer of microRNA by exosomes. Blood 2012 119 3 646 648 10.1182/blood‑2011‑11‑389478 22262739
    [Google Scholar]
  74. Villarroya-Beltri C. Gutiérrez-Vázquez C. Sánchez-Cabo F. Pérez-Hernández D. Vázquez J. Martin-Cofreces N. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 2013 4 2980 10.1038/ncomms3980 24356509
    [Google Scholar]
  75. Santangelo L. Giurato G. Cicchini C. The RNA-binding protein SYNCRIP is a component of the hepatocyte exosomal machinery controlling microRNA sorting. Cell Rep. 2016 17 3 799 808 10.1016/j.celrep.2016.09.031 27732855
    [Google Scholar]
  76. Carnino J.M. Ni K. Jin Y. Post-translational modification regulates formation and cargo-loading of extracellular vesicles. Front. Immunol. 2020 11 948 10.3389/fimmu.2020.00948 32528471
    [Google Scholar]
  77. Kojima R. Bojar D. Rizzi G. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat. Commun. 2018 9 1 1305 10.1038/s41467‑018‑03733‑8 29610454
    [Google Scholar]
  78. Sutaria D.S. Jiang J. Elgamal O.A. Low active loading of cargo into engineered extracellular vesicles results in inefficient miRNA mimic delivery. J. Extracell. Vesicles 2017 6 1 1333882 10.1080/20013078.2017.1333882 28717424
    [Google Scholar]
  79. Masliah G. Barraud P. Allain F.H. RNA recognition by double-stranded RNA binding domains: A matter of shape and sequence. Cell. Mol. Life Sci. 2013 70 11 1875 1895 10.1007/s00018‑012‑1119‑x 22918483
    [Google Scholar]
  80. Diao Y. Wang G. Zhu B. Loading of “cocktail siRNAs” into extracellular vesicles via TAT-DRBD peptide for the treatment of castration-resistant prostate cancer. Cancer Biol. Ther. 2022 23 1 163 172 10.1080/15384047.2021.2024040 35171081
    [Google Scholar]
  81. Hade M.D. Suire C.N. Suo Z. An effective peptide-based platform for efficient exosomal loading and cellular delivery of a microRNA. ACS Appl. Mater. Interfaces 2023 15 3 3851 3866 10.1021/acsami.2c20728 36638205
    [Google Scholar]
  82. Hade M.D. Suire C.N. Suo Z. Significant enhancement of fibroblast migration, invasion, and proliferation by exosomes loaded with human fibroblast growth factor 1. ACS Appl. Mater. Interfaces 2024 16 2 1969 1984 10.1021/acsami.3c10350 38181175
    [Google Scholar]
  83. Li Z. Zhou X. Wei M. In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. Nano Lett. 2019 19 1 19 28 10.1021/acs.nanolett.8b02689 30517011
    [Google Scholar]
  84. Li Z. Zhou X. Gao X. Fusion protein engineered exosomes for targeted degradation of specific RNAs in lysosomes: A proof‐of‐concept study. J. Extracell. Vesicles 2020 9 1 1816710 10.1080/20013078.2020.1816710 33133429
    [Google Scholar]
  85. Weidberg H. Shpilka T. Shvets E. Abada A. Shimron F. Elazar Z. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev. Cell 2011 20 4 444 454 10.1016/j.devcel.2011.02.006 21497758
    [Google Scholar]
  86. Leidal A.M. Huang H.H. Marsh T. The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles. Nat. Cell Biol. 2020 22 2 187 199 10.1038/s41556‑019‑0450‑y 31932738
    [Google Scholar]
  87. Gardner J.O. Leidal A.M. Nguyen T.A. Debnath J. LC3-dependent EV loading and secretion (LDELS) promotes TFRC (transferrin receptor) secretion via extracellular vesicles. Autophagy 2023 19 5 1551 1561 10.1080/15548627.2022.2140557 36286616
    [Google Scholar]
  88. Choi H. Yim H. Park C. Targeted delivery of exosomes armed with anti-cancer therapeutics. Membranes 2022 12 1 85 10.3390/membranes12010085 35054611
    [Google Scholar]
  89. Lee Y.J. Shin K.J. Chae Y.C. Regulation of cargo selection in exosome biogenesis and its biomedical applications in cancer. Exp. Mol. Med. 2024 56 4 877 889 10.1038/s12276‑024‑01209‑y 38580812
    [Google Scholar]
  90. Chavda V.P. Sugandhi V.V. Pardeshi C.V. Engineered exosomes for cancer theranostics: Next-generation tumor targeting. J. Drug Deliv. Sci. Technol. 2023 85 104579 10.1016/j.jddst.2023.104579
    [Google Scholar]
  91. Zhu Q. Heon M. Zhao Z. He M. Microfluidic engineering of exosomes: Editing cellular messages for precision therapeutics. Lab Chip 2018 18 12 1690 1703 10.1039/C8LC00246K 29780982
    [Google Scholar]
  92. Baek G. Choi H. Kim Y. Lee H.C. Choi C. Mesenchymal stem cell-derived extracellular vesicles as therapeutics and as a drug delivery platform. Stem Cells Transl. Med. 2019 8 9 880 886 10.1002/sctm.18‑0226 31045328
    [Google Scholar]
  93. Rayamajhi S. Aryal S. Surface functionalization strategies of extracellular vesicles. J. Mater. Chem. B Mater. Biol. Med. 2020 8 21 4552 4569 10.1039/D0TB00744G 32377649
    [Google Scholar]
  94. Théry C. Zitvogel L. Amigorena S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002 2 8 569 579 10.1038/nri855 12154376
    [Google Scholar]
  95. Buschow S.I. Nolte-’t Hoen E.N.M. Van Niel G. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 2009 10 10 1528 1542 10.1111/j.1600‑0854.2009.00963.x 19682328
    [Google Scholar]
  96. Raposo G. Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J. Cell Biol. 2013 200 4 373 383 10.1083/jcb.201211138 23420871
    [Google Scholar]
  97. Besse B. Charrier M. Lapierre V. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. OncoImmunology 2016 5 4 e1071008 10.1080/2162402X.2015.1071008 27141373
    [Google Scholar]
  98. Blanchard N. Lankar D. Faure F. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J. Immunol. 2002 168 7 3235 3241 10.4049/jimmunol.168.7.3235 11907077
    [Google Scholar]
  99. Rialland P. Lankar D. Raposo G. Bonnerot C. Hubert P. BCR‐bound antigen is targeted to exosomes in human follicular lymphoma B‐cells. Biol. Cell 2006 98 8 491 501 10.1042/BC20060027 16677129
    [Google Scholar]
  100. Lugini L. Cecchetti S. Huber V. Immune surveillance properties of human NK cell-derived exosomes. J. Immunol. 2012 189 6 2833 2842 10.4049/jimmunol.1101988 22904309
    [Google Scholar]
  101. Tzortzakaki E. Spilianakis C. Zika E. Kretsovali A. Papamatheakis J. Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways. Mol. Endocrinol. 2003 17 12 2509 2518 10.1210/me.2002‑0439 12933903
    [Google Scholar]
  102. Lee Y.S. Kim S.H. Cho J.A. Kim C.W. Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects. Exp. Mol. Med. 2011 43 5 281 290 10.3858/emm.2011.43.5.029 21464590
    [Google Scholar]
  103. Grapp M. Wrede A. Schweizer M. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat. Commun. 2013 4 1 2123 10.1038/ncomms3123 23828504
    [Google Scholar]
  104. Mohanty V. Siddiqui M.R. Tomita T. Mayanil C.S. Folate receptor alpha is more than just a folate transporter. Neurogenesis 2017 4 1 e1263717 10.1080/23262133.2016.1263717 28229085
    [Google Scholar]
  105. Low P.S. Kularatne S.A. Folate-targeted therapeutic and imaging agents for cancer. Curr. Opin. Chem. Biol. 2009 13 3 256 262 10.1016/j.cbpa.2009.03.022 19419901
    [Google Scholar]
  106. Sega E.I. Low P.S. Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev. 2008 27 4 655 664 10.1007/s10555‑008‑9155‑6 18523731
    [Google Scholar]
  107. Cheung A. Bax H.J. Josephs D.H. Targeting folate receptor alpha for cancer treatment. Oncotarget 2016 7 32 52553 52574 10.18632/oncotarget.9651 27248175
    [Google Scholar]
  108. Alvarez-Erviti L. Seow Y. Yin H. Betts C. Lakhal S. Wood M.J.A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011 29 4 341 345 10.1038/nbt.1807 21423189
    [Google Scholar]
  109. Kim H. Yun N. Mun D. Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes. Biochem. Biophys. Res. Commun. 2018 499 4 803 808 10.1016/j.bbrc.2018.03.227 29621543
    [Google Scholar]
  110. Ferreira J.V. da Rosa Soares A. Ramalho J. LAMP2A regulates the loading of proteins into exosomes. Sci. Adv. 2022 8 12 eabm1140 10.1126/sciadv.abm1140 35333565
    [Google Scholar]
  111. Louis Jeune V. Joergensen J.A. Hajjar R.J. Weber T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods 2013 24 2 59 67 10.1089/hgtb.2012.243 23442094
    [Google Scholar]
  112. Li X. La Salvia S. Liang Y. Extracellular vesicle–encapsulated adeno-associated viruses for therapeutic gene delivery to the heart. Circulation 2023 148 5 405 425 10.1161/CIRCULATIONAHA.122.063759 37409482
    [Google Scholar]
  113. Deshetty U.M. Sil S. Buch S. Gene therapy for the heart: Encapsulated viruses to the rescue. Extracell Vesicles Circ Nucleic Acids 2024 5 1 114 118 10.20517/evcna.2023.70 39698416
    [Google Scholar]
  114. Saad F.A. Saad J.F. Siciliano G. Merlini L. Angelini C. Duchenne muscular dystrophy gene therapy. Curr. Gene Ther. 2024 24 1 17 28 10.2174/1566523223666221118160932 36411557
    [Google Scholar]
  115. Jafari D. Shajari S. Jafari R. Designer exosomes: A new platform for biotechnology therapeutics. BioDrugs 2020 34 5 567 586 10.1007/s40259‑020‑00434‑x 32754790
    [Google Scholar]
  116. György B. Sage C. Indzhykulian A.A. Rescue of hearing by gene delivery to inner-ear hair cells using exosome-associated AAV. Mol. Ther. 2017 25 2 379 391 10.1016/j.ymthe.2016.12.010 28082074
    [Google Scholar]
  117. Luketic L. Delanghe J. Sobol P.T. Antigen presentation by exosomes released from peptide-pulsed dendritic cells is not suppressed by the presence of active CTL. J. Immunol. 2007 179 8 5024 5032 10.4049/jimmunol.179.8.5024 17911587
    [Google Scholar]
  118. Mallegol J. Van Niel G. Lebreton C. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 2007 132 5 1866 1876 10.1053/j.gastro.2007.02.043 17484880
    [Google Scholar]
  119. Petersen S.H. Odintsova E. Haigh T.A. Rickinson A.B. Taylor G.S. Berditchevski F. The role of tetraspanin CD63 in antigen presentation via MHC class II. Eur. J. Immunol. 2011 41 9 2556 2561 10.1002/eji.201141438 21660937
    [Google Scholar]
  120. Lindenbergh M.F.S. Wubbolts R. Borg E.G.F. van ’T Veld EM, Boes M, Stoorvogel W. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. J. Extracell. Vesicles 2020 9 1 1798606 10.1080/20013078.2020.1798606 32944186
    [Google Scholar]
  121. Feng D. Zhao W.L. Ye Y.Y. Cellular internalization of exosomes occurs through phagocytosis. Traffic 2010 11 5 675 687 10.1111/j.1600‑0854.2010.01041.x 20136776
    [Google Scholar]
  122. Lai C.P. Mardini O. Ericsson M. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 2014 8 1 483 494 10.1021/nn404945r 24383518
    [Google Scholar]
  123. Yang Z. Shi J. Xie J. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 2019 4 1 69 83 10.1038/s41551‑019‑0485‑1 31844155
    [Google Scholar]
  124. Takahashi Y. Nishikawa M. Shinotsuka H. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J. Biotechnol. 2013 165 2 77 84 10.1016/j.jbiotec.2013.03.013 23562828
    [Google Scholar]
  125. van Rooijen N. Sanders A. van den Berg T.K. Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J. Immunol. Methods 1996 193 1 93 99 10.1016/0022‑1759(96)00056‑7 8690935
    [Google Scholar]
  126. Matsumoto A. Takahashi Y. Chang H.Y. Blood concentrations of small extracellular vesicles are determined by a balance between abundant secretion and rapid clearance. J. Extracell. Vesicles 2020 9 1 1696517 10.1080/20013078.2019.1696517 31807238
    [Google Scholar]
  127. Brown S. Heinisch I. Ross E. Shaw K. Buckley C.D. Savill J. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 2002 418 6894 200 203 10.1038/nature00811 12110892
    [Google Scholar]
  128. Gordon S.R. Maute R.L. Dulken B.W. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017 545 7655 495 499 10.1038/nature22396 28514441
    [Google Scholar]
  129. Kamerkar S. LeBleu V.S. Sugimoto H. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017 546 7659 498 503 10.1038/nature22341 28607485
    [Google Scholar]
  130. Weiskopf K. Cancer immunotherapy targeting the CD47/SIRPα axis. Eur. J. Cancer 2017 76 100 109 10.1016/j.ejca.2017.02.013 28286286
    [Google Scholar]
  131. Barkal A.A. Brewer R.E. Markovic M. Kowarsky M. Barkal S.A. Zaro B.W. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 2019 572 5 392 396 10.1038/s41586‑019‑1456‑0
    [Google Scholar]
  132. Barkal A.A. Weiskopf K. Kao K.S. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 2018 19 1 76 84 10.1038/s41590‑017‑0004‑z 29180808
    [Google Scholar]
  133. Cosman D. Fanger N. Borges L. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 1997 7 2 273 282 10.1016/S1074‑7613(00)80529‑4 9285411
    [Google Scholar]
  134. Cheng H. Mohammed F. Nam G. Crystal structure of leukocyte Ig-like receptor LILRB4 (ILT3/LIR-5/CD85k): A myeloid inhibitory receptor involved in immune tolerance. J. Biol. Chem. 2011 286 20 18013 18025 10.1074/jbc.M111.221028 21454581
    [Google Scholar]
  135. Baía D. Pou J. Jones D. Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers. Eur. J. Immunol. 2016 46 7 1681 1690 10.1002/eji.201546149 27109306
    [Google Scholar]
  136. Hough M.R. Rosten P.M. Sexton T.L. Kay R. Humphries R.K. Mapping of CD24 and homologous sequences to multiple chromosomal loci. Genomics 1994 22 1 154 161 10.1006/geno.1994.1356 7959762
    [Google Scholar]
  137. Fang X. Zheng P. Tang J. Liu Y. CD24: From A to Z. Cell. Mol. Immunol. 2010 7 2 100 103 10.1038/cmi.2009.119 20154703
    [Google Scholar]
  138. Woodfin A. Voisin M.B. Nourshargh S. PECAM-1: A multi-functional molecule in inflammation and vascular biology. Arterioscler. Thromb. Vasc. Biol. 2007 27 12 2514 2523 10.1161/ATVBAHA.107.151456 17872453
    [Google Scholar]
  139. Oldenborg P.A. CD47: A cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease. ISRN Hematol. 2013 2013 1 19 10.1155/2013/614619 23401787
    [Google Scholar]
  140. Matozaki T. Murata Y. Okazawa H. Ohnishi H. Functions and molecular mechanisms of the CD47–SIRPα signalling pathway. Trends Cell Biol. 2009 19 2 72 80 10.1016/j.tcb.2008.12.001 19144521
    [Google Scholar]
  141. Suzuki E. Umezawa K. Inhibition of macrophage activation and phagocytosis by a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin. Biomed. Pharmacother. 2006 60 9 578 586 10.1016/j.biopha.2006.07.089 16978829
    [Google Scholar]
  142. Okazaki T. Honjo T. The PD-1–PD-L pathway in immunological tolerance. Trends Immunol. 2006 27 4 195 201 10.1016/j.it.2006.02.001 16500147
    [Google Scholar]
  143. Keir M.E. Butte M.J. Freeman G.J. Sharpe A.H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 2008 26 1 677 704 10.1146/annurev.immunol.26.021607.090331 18173375
    [Google Scholar]
  144. Kong W. Li X. Guo X. Ultrasound-assisted CRISPRi-exosome for epigenetic modification of α-synuclein gene in a mouse model of Parkinson’s disease. ACS Nano 2024 18 11 7837 7851 10.1021/acsnano.3c05864 38437635
    [Google Scholar]
  145. Zhang L. Lin Y. Li S. Guan X. Jiang X. In situ reprogramming of tumor‐associated macrophages with internally and externally engineered exosomes. Angew. Chem. Int. Ed. 2023 62 11 e202217089 10.1002/anie.202217089 36658634
    [Google Scholar]
/content/journals/cgt/10.2174/0115665232409032250908114520
Loading
Precision Medicine: Design of Immune Inert Exosomes for Targeted Gene Delivery
Bentham Science Publishers ; https://doi.org/10.2174/0115665232409032250908114520
/content/journals/cgt/10.2174/0115665232409032250908114520
/content/journals/cgt/10.2174/0115665232409032250908114520
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: extracellular vesicles ; Designer exosomes ; blood-brain barrier ; tailored cargos ; smart exosomes ; invisible exosomes

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test