Nucleic acid functionalized extracellular vesicles as promising therapeutic systems for nanomedicine

Abstract

Extracellular vesicles (EVs), as natural carriers, are regarded as a new star in nanomedicine due to their excellent biocompatibility, fascinating physicochemical properties, and unique biological regulatory functions. However, there are still some challenges to using natural EVs, including poor targeting ability and the clearance from circulation, which may limit their further development and clinical use. Nucleic acid has the functions of programmability, targeting, gene therapy, and immune regulation. Owing to the engineering design and modification by integrating functional nucleic acid, EVs offer excellent performances as a therapeutic system in vivo. This review briefly introduces the function and mechanism of nucleic acid in the diagnosis and treatment of diseases. Then, the strategies of nucleic acid-functionalized EVs are summarized and the latest progress of nucleic acid-functionalized EVs in nanomedicine is highlighted. Finally, the challenges and prospects of nucleic acid-functionalized EVs as a promising diagnostic system are proposed.

Keywords

Extracellular vesicles / nucleic acid / nanomedicine / mRNA vaccine / aptamer

References

[1] Théry C,Amigorena S.Exosomes: composition, biogenesis and function.Nat Rev Immunol2002;2:569-79

[2] Meckes DG Jr,Marquitz AR,Edwards RH.Human tumor virus utilizes exosomes for intercellular communication.Proc Natl Acad Sci U S A2010;107:20370-5 PMCID:PMC2996715

[3] Umezu T,Kuroda M.Leukemia cell to endothelial cell communication via exosomal miRNAs.Oncogene2013;32:2747-55

[4] der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles.Pharmacol Rev2012;64:676-705

[5] Herrmann IK,Fuhrmann G.Extracellular vesicles as a next-generation drug delivery platform.Nat Nanotechnol2021;16:748-59

[6] Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities.Nat Rev Drug Discov2013;12:347-57

[7] Li F,Chen A.Combined transplantation of neural stem cells and bone marrow mesenchymal stem cells promotes neuronal cell survival to alleviate brain damage after cardiac arrest via microRNA-133b incorporated in extracellular vesicles.Aging (Albany NY)2021;13:262-78 PMCID:PMC7835040

[8] Wu P,Ocansey DKW,Qian H.Extracellular vesicles: a bright star of nanomedicine.Biomaterials2021;269:120467

[9] Liu C,He D.Therapeutic applications of extracellular vesicles for myocardial repair.Front Cardiovasc Med2021;8:758050 PMCID:PMC8695616

[10] Fan Z,Xue Y.Reversing cold tumors to hot: an immunoadjuvant-functionalized metal-organic framework for multimodal imaging-guided synergistic photo-immunotherapy.Bioact Mater2021;6:312-25 PMCID:PMC7475520

[11] Akinc A,Manoharan M.The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs.Nat Nanotechnol2019;14:1084-7

[12] Chen Y,Pan W.Polyvalent spherical aptamer engineered macrophages: X-ray-actuated phenotypic transformation for tumor immunotherapy.Chem Sci2021;12:13817-24 PMCID:PMC8549783

[13] Gao P,Li N.Fluorescent probes for organelle-targeted bioactive species imaging.Chem Sci2019;10:6035-71 PMCID:PMC6585876

[14] Wu Y,Zeng Q,Xing D.Light-responsive charge-reversal nanovector for high-efficiency in vivo CRISPR/Cas9 gene editing with controllable location and time.Nano Res2020;13:2399-406

[15] Wang X,Yue Q.Liquid exfoliation of TiN nanodots as novel sonosensitizers for photothermal-enhanced sonodynamic therapy against cancer.Nano Today2021;39:101170

[16] Zhou L,Hao M.An injectable and biodegradable nano-photothermal DNA hydrogel enhances penetration and efficacy of tumor therapy.Biomater Sci2021;9:4904-21

[17] Lu C,Xing D.Photo-enhancement of macrophage phagocytic activity via Rac1-mediated signaling pathway: implications for bacterial infection.Int J Biochem Cell Biol2016;78:206-16

[18] Liu Y,Zhou Y.Self-circulating electrochemiluminescence chip for sensitive detection of circulating tumour nucleic acids in blood.Sens Actuators B Chem2019;301:127088

[19] Zhao Z,Zhan X.Cascaded electrochemiluminescence signal amplifier for the detection of telomerase activity from tumor cells and tissues.Theranostics2018;8:5625-33 PMCID:PMC6276299

[20] Oh YK.siRNA delivery systems for cancer treatment.Adv Drug Deliv Rev2009;61:850-62

[21] Gao P,Wan X.A COF-based anti-interference nanoplatform for intracellular nucleic acid imaging.Chem Commun (Camb)2020;56:14267-70

[22] Gao P,Chen Y.Multicolor covalent organic framework-DNA nanoprobe for fluorescence imaging of biomarkers with different locations in living cells.Anal Chem2021;93:13734-41

[23] Gao P,Liu X.Nucleic acid-gated covalent organic frameworks for cancer-specific imaging and drug release.Anal Chem2021;93:11751-7

[24] Xu CF,Shen S,Yang X.Development of “CLAN” nanomedicine for nucleic acid therapeutics.Small2019;15:e1900055

[25] Bonanni A,Pumera M.Nucleic acid functionalized graphene for biosensing.Chemistry2012;18:1668-73

[26] Sacks D,Campbell BCV.From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), European Stroke Organization (ESO), European Stroke Organization (ESO), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO)Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke.Int J Stroke2018;13:612-32

[27] Tapsin S,Shen Y.Genome-wide identification of natural RNA aptamers in prokaryotes and eukaryotes.Nat Commun2018;9:1289 PMCID:PMC5876405

[28] Zhu G.Aptamer-based targeted therapy.Adv Drug Deliv Rev2018;134:65-78 PMCID:PMC6239901

[29] Nimjee SM,Becker RC.Aptamers as therapeutics.Annu Rev Pharmacol Toxicol2017;57:61-79 PMCID:PMC6035745

[30] Gefen T,Muharemagic D,Patel S.A TIM-3 oligonucleotide aptamer enhances T cell functions and potentiates tumor immunity in mice.Mol Ther2017;25:2280-8 PMCID:PMC5628791

[31] Panigaj M,Ke W.Aptamers as modular components of therapeutic nucleic acid nanotechnology.ACS Nano2019;13:12301-21 PMCID:PMC7382785

[32] Wang J,Luo Y.In vitro selection of a DNA aptamer by cell-SELEX as a molecular probe for cervical cancer recognition and imaging.J Mol Evol2019;87:72-82

[33] Liu M,Tan T.An aptamer-based probe for molecular subtyping of breast cancer.Theranostics2018;8:5772-83 PMCID:PMC6276286

[34] Wang L,Gao L.A DNA aptamer for binding and inhibition of DNA methyltransferase 1.Nucleic Acids Res2019;47:11527-37 PMCID:PMC7145629

[35] Zheng J,Yu X,Liu HY.Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth.Theranostics2017;7:1373-88 PMCID:PMC5399600

[36] Li Y,Tan Y.A new paradigm for artesunate anticancer function: considerably enhancing the cytotoxicity via conjugating artesunate with aptamer.Signal Transduct Target Ther2021;6:327 PMCID:PMC8429419

[37] Mergny JL.DNA quadruple helices in nanotechnology.Chem Rev2019;119:6290-325

[38] Krishnan Y.Introduction: nucleic acid nanotechnology.Chem Rev2019;119:6271-2

[39] Hu Q,Wang L,Fan C.DNA nanotechnology-enabled drug delivery systems.Chem Rev2019;119:6459-506

[40] Hong F,Liu Y.DNA origami: scaffolds for creating higher order structures.Chem Rev2017;117:12584-640

[41] Jiang Q,Liu J,Ding B.Rationally designed DNA-origami nanomaterials for drug delivery in vivo.Adv Mater2019;31:e1804785

[42] Ge Z,Wu G.DNA origami-enabled engineering of ligand-drug conjugates for targeted drug delivery.Small2020;16:e1904857

[43] Zhang T,Frank K.3D DNA origami crystals.Adv Mater2018;30:e1800273

[44] Li S,Liu S.A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo.Nat Biotechnol2018;36:258-64

[45] Ma W,Zhang Y.An intelligent DNA nanorobot with in vitro enhanced protein lysosomal degradation of HER2.Nano Lett2019;19:4505-17

[46] Jiang Q,Nangreave J.DNA origami as a carrier for circumvention of drug resistance.J Am Chem Soc2012;134:13396-403

[47] Jiang Q,Yin PA.Circularly polarized luminescence of achiral cyanine molecules assembled on DNA templates.J Am Chem Soc2019;141:9490-4

[48] Ijäs H,Heuer-Jungemann A.Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release.Nucleic Acids Res2021;49:3048-62 PMCID:PMC8034656

[49] Xu T,Sun Y.DNA origami frameworks enabled self-protective siRNA delivery for dual enhancement of chemo-photothermal combination therapy.Small2021;17:e2101780

[50] Wang Z,Liu Q.A tubular DNA nanodevice as a siRNA/chemo-drug co-delivery vehicle for combined cancer therapy.Angew Chem Int Ed Engl2021;60:2594-8

[51] Wang ST,Xuan S.DNA origami protection and molecular interfacing through engineered sequence-defined peptoids.Proc Natl Acad Sci U S A2020;117:6339-48 PMCID:PMC7104344

[52] Liu J,Liu S.A DNA-based nanocarrier for efficient gene delivery and combined cancer therapy.Nano Lett2018;18:3328-34

[53] Wu T,Liu M.A nanobody-conjugated DNA nanoplatform for targeted platinum-drug delivery.Angew Chem2019;131:14362-6

[54] Liu X,Zhou Y,Jiang W.Multifunctional molecular beacons-modified gold nanoparticle as a nanocarrier for synergistic inhibition and in situ imaging of drug-resistant-related mRNAs in living cells.ACS Appl Mater Interfaces2019;11:35548-55

[55] Ma Y,Zhang M.A telomerase-specific doxorubicin-releasing molecular beacon for cancer theranostics.Angew Chem Int Ed Engl2016;55:3304-8

[56] Wang J,Liu H.Clamped hybridization chain reactions for the self-assembly of patterned DNA hydrogels.Angew Chem Int Ed Engl2017;56:2171-5

[57] Zhang J,Pan G.Injectable drug-conjugated DNA hydrogel for local chemotherapy to prevent tumor recurrence.ACS Appl Mater Interfaces2020;12:21441-9

[58] High KA.Gene therapy.N Engl J Med2019;381:455-64

[59] Kulkarni JA,Thomson SB.The current landscape of nucleic acid therapeutics.Nat Nanotechnol2021;16:630-43

[60] Kusano KF,Murayama T.Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.Nat Med2005;11:1197-204

[61] Fellmann C,Lin PC,Corn JE.Cornerstones of CRISPR-Cas in drug discovery and therapy.Nat Rev Drug Discov2017;16:89-100 PMCID:PMC5459481

[62] Bartok E.Immune sensing mechanisms that discriminate self from altered self and foreign nucleic acids.Immunity2020;53:54-77 PMCID:PMC7359798

[63] Deng C,Jia M.Tumors and their microenvironment dual-targeting chemotherapy with local immune adjuvant therapy for effective antitumor immunity against breast cancer.Adv Sci (Weinh)2019;6:1801868 PMCID:PMC6425447

[64] Lai C,Ye F.The enhanced antitumor-specific immune response with mannose- and CpG-ODN-coated liposomes delivering TRP2 peptide.Theranostics2018;8:1723-39 PMCID:PMC5858178

[65] Moreira D,Zhao X.STAT3 inhibition combined with CpG immunostimulation activates antitumor immunity to eradicate genetically distinct castration-resistant prostate cancers.Clin Cancer Res2018;24:5948-62 PMCID:PMC6279477

[66] Charlebois R,Allard D.PolyI:C and CpG synergize with anti-ErbB2 mAb for treatment of breast tumors resistant to immune checkpoint inhibitors.Cancer Res2017;77:312-9

[67] Sagiv-Barfi I,Levy S.Eradication of spontaneous malignancy by local immunotherapy.Sci Transl Med2018;10:eaan4488 PMCID:PMC5997264

[68] Ni Q,Liu Y.A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer.Sci Adv2020;6:eaaw6071 PMCID:PMC7080439

[69] Morishita M,Matsumoto A,Takakura Y.Exosome-based tumor antigens-adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA.Biomaterials2016;111:55-65

[70] Yildirim M,Turay N.TLR ligand loaded exosome mediated immunotherapy of established mammary Tumor in mice.Immunol Lett2021;239:32-41

[71] Naour J, Galluzzi L, Zitvogel L, Kroemer G, Vacchelli E. Trial watch: TLR3 agonists in cancer therapy.Oncoimmunology2020;9:1771143 PMCID:PMC7466857

[72] Qiu N,Wang J.Tumor-associated macrophage and tumor-cell dually transfecting polyplexes for efficient interleukin-12 cancer gene therapy.Adv Mater2021;33:e2006189

[73] Chiocca EA,Lukas RV.Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: results of a phase 1 trial.Sci Transl Med2019;11:eaaw5680 PMCID:PMC7286430

[74] Qin F,Chen H.A guide to nucleic acid vaccines in the prevention and treatment of infectious diseases and cancers: from basic principles to current applications.Front Cell Dev Biol2021;9:633776 PMCID:PMC8185206

[75] Ho PP,Mourkioti F.Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy.Proc Natl Acad Sci U S A2018;115:E9182-91 PMCID:PMC6166850

[76] Parks RJ.Building immune tolerance through DNA vaccination.Proc Natl Acad Sci U S A2018;115:9652-4 PMCID:PMC6166841

[77] Jackson NAC,Casimiro D,DeRosa F.The promise of mRNA vaccines: a biotech and industrial perspective.NPJ Vaccines2020;5:11 PMCID:PMC7000814

[78] Espeseth AS,Citron MP.Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection.NPJ Vaccines2020;5:16 PMCID:PMC7021756

[79] Van Hoecke L,Dewitte H.mRNA in cancer immunotherapy: beyond a source of antigen.Mol Cancer2021;20:48 PMCID:PMC7926200

[80] Heine A,Brossart P.Clinical and immunological effects of mRNA vaccines in malignant diseases.Mol Cancer2021;20:52 PMCID:PMC7957288

[81] Wang Y,Luo J,Wei Y.mRNA vaccine: a potential therapeutic strategy.Mol Cancer2021;20:33 PMCID:PMC7884263

[82] Miao L,Huang L.mRNA vaccine for cancer immunotherapy.Mol Cancer2021;20:41 PMCID:PMC7905014

[83] Park JW,Liu Y.mRNA vaccines for COVID-19: what, why and how.Int J Biol Sci2021;17:1446-60 PMCID:PMC8071766

[84] Polack FP,Kitchin N.C4591001 Clinical Trial GroupSafety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med2020;383:2603-15 PMCID:PMC7745181

[85] Vrieze J. Pfizer’s vaccine raises allergy concerns.Science2021;371:10-1

[86] Hall VJ,Saei A.COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.Lancet2021;397:1725-35 PMCID:PMC8064668

[87] Haas EJ,Mclaughlin JM.Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.Lancet2021;397:1819-29 PMCID:PMC8099315

[88] Alberer M,Hong HS.Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial.Lancet2017;390:1511-20

[89] Kojima R,Rizzi G.Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment.Nat Commun2018;9:1305 PMCID:PMC5880805

[90] Yang J,Hou L.Therapeutic effects of simultaneous delivery of nerve growth factor mRNA and protein via exosomes on cerebral ischemia.Mol Ther Nucleic Acids2020;21:512-22 PMCID:PMC7365960

[91] Kim SM,Oh SJ,Seo M.Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting.J Control Release2017;266:8-16

[92] Didiot MC,Coles AH.Exosome-mediated delivery of hydrophobically modified siRNA for huntingtin mRNA silencing.Mol Ther2016;24:1836-47 PMCID:PMC5112038

[93] Wan Y,Zhu C.Aptamer-conjugated extracellular nanovesicles for targeted drug delivery.Cancer Res2018;78:798-808 PMCID:PMC5811376

[94] Fan Z,Lin J,Huang X.Functionalized DNA enables programming exosomes/vesicles for tumor imaging and therapy.Small2019;15:e1903761

[95] Wang J,Dong Y.Designer exosomes enabling tumor targeted efficient chemo/gene/photothermal therapy.Biomaterials2021;276:121056

[96] Zhao L,Gan Y,Chen H.Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis.J Control Release2020;318:1-15

[97] Yu G,Kang YY.Comparative evaluation of cell- and serum-derived exosomes to deliver immune stimulators to lymph nodes.Biomaterials2018;162:71-81

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

[99] Zhupanyn P,Büch T.Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo.J Control Release2020;319:63-76

[100] Lamichhane TN,Patel DB.Oncogene knockdown via active loading of small RNAs into extracellular vesicles by sonication.Cell Mol Bioeng2016;9:315-24 PMCID:PMC5084850

[101] Wang H,Wan K.In situ multiplex detection of serum exosomal microRNAs using an all-in-one biosensor for breast cancer diagnosis.Analyst2020;145:3289-96

[102] Lee JH,Kwon MH,Rhee WJ.In situ single step detection of exosome microRNA using molecular beacon.Biomaterials2015;54:116-25

[103] Lin Y,Gu W.Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs.Adv Sci (Weinh)2018;5:1700611 PMCID:PMC5908366

[104] Stremersch S,Van Wonterghem E,De Smedt SC.Comparing exosome-like vesicles with liposomes for the functional cellular delivery of small RNAs.J Control Release2016;232:51-61

[105] Yang X,Peng H.Eradicating intracellular MRSA via targeted delivery of lysostaphin and vancomycin with mannose-modified exosomes.J Control Release2021;329:454-67

[106] An Y,Zhu Y,He P.An ultrasensitive electrochemical aptasensor for the determination of tumor exosomes based on click chemistry.Biosens Bioelectron2019;142:111503

[107] Smyth T,Payton NM.Surface functionalization of exosomes using click chemistry.Bioconjug Chem2014;25:1777-84 PMCID:PMC4198107

[108] Wang B,Huuskes BM.Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis.Mol Ther2016;24:1290-301 PMCID:PMC5088767

[109] Yu X,Han B.Extracellular vesicle-mediated delivery of circDYM alleviates CUS-induced depressive-like behaviours.J Extracell Vesicles2022;11:e12185 PMCID:PMC8758833

[110] Wang Y,Tian B.Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer.Theranostics2017;7:1360-72 PMCID:PMC5399599

[111] Reshke R,Savard A.Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone.Nat Biomed Eng2020;4:52-68

[112] O’Loughlin AJ,de Jong OG.Functional delivery of lipid-conjugated siRNA by extracellular vesicles.Mol Ther2017;25:1580-7 PMCID:PMC5498810

[113] Biscans A,Echeverria D.Hydrophobicity of lipid-conjugated siRNAs predicts productive loading to small extracellular vesicles.Mol Ther2018;26:1520-8 PMCID:PMC5986735

[114] Zheng Z,Xu C,Guo P.Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping.J Control Release2019;311-312:43-9 PMCID:PMC6874920

[115] Pi F,Lee TJ.Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression.Nat Nanotechnol2018;13:82-9 PMCID:PMC5762263

[116] Yang Z,Xie J.Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation.Nat Biomed Eng2020;4:69-83 PMCID:PMC7080209

[117] Zhang S,Wang Y.Selective encapsulation of therapeutic mRNA in engineered extracellular vesicles by DNA aptamer.Nano Lett2021;21:8563-70

[118] Sedlik C,Torrieri-Dramard L.Different immunogenicity but similar antitumor efficacy of two DNA vaccines coding for an antigen secreted in different membrane vesicle-associated forms.J Extracell Vesicles2014;3:24646 PMCID:PMC4149746

[119] Kanada M,Hardy JW.Microvesicle-mediated delivery of minicircle DNA results in effective gene-directed enzyme prodrug cancer therapy.Mol Cancer Ther2019;18:2331-42 PMCID:PMC6891168

[120] Zou J,Liu X.Aptamer-functionalized exosomes: elucidating the cellular uptake mechanism and the potential for cancer-targeted chemotherapy.Anal Chem2019;91:2425-30 PMCID:PMC6662586

[121] Mathiyalagan P.Exosomes-based gene therapy for microRNA delivery.Methods Mol Biol2017;1521:139-52 PMCID:PMC5502074

[122] Guo S,Betzer O.Intranasal delivery of mesenchymal stem cell derived exosomes loaded with phosphatase and tensin homolog siRNA repairs complete spinal cord injury.ACS Nano2019;13:10015-28

[123] Tang J,Zhang Z.Injection-free delivery of MSC-derived extracellular vesicles for myocardial infarction therapeutics.Adv Healthc Mater2021;:e2100312

[124] Zhang Y,Hao Z.Umbilical mesenchymal stem cell-derived exosome-encapsulated hydrogels accelerate bone repair by enhancing angiogenesis.ACS Appl Mater Interfaces2021;13:18472-87

[125] Gang D,Zhu S,Nasser MI.Application of mesenchymal stem cell-derived exosomes in kidney diseases.Cell Immunol2021;364:104358

[126] Tsai SJ,Sedgwick A.Exosome-mediated mRNA delivery for SARS-CoV-2 vaccination.bioRxiv2021;