{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:11:41Z","timestamp":1790212301294,"version":"4.1.0"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,26]],"date-time":"2020-04-26T00:00:00Z","timestamp":1587859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DA047178"],"award-info":[{"award-number":["DA047178"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by the World Health Organization (WHO). Full-length genome sequences of SARS-CoV-2 showed 79.6% sequence identity to SARS-CoV, with 96% identity to a bat coronavirus at the whole-genome level. COVID-19 has caused over 133,000 deaths and there are over 2 million total confirmed cases as of 15 April 2020. Current treatment plans are still under investigation due to a lack of understanding of COVID-19. One potential mechanism to slow disease progression is the use of antiviral drugs to either block the entry of the virus or interfere with viral replication and maturation. Currently, antiviral drugs, including chloroquine\/hydroxychloroquine, remdesivir, and lopinavir\/ritonavir, have shown effective inhibition of SARS-CoV-2 in vitro. Due to the high dose needed and narrow therapeutic window, many patients are experiencing severe side effects with the above drugs. Hence, repurposing these drugs with a proper formulation is needed to improve the safety and efficacy for COVID-19 treatment. Extracellular vesicles (EVs) are a family of natural carriers in the human body. They play a critical role in cell-to-cell communications. EVs can be used as unique drug carriers to deliver protease inhibitors to treat COVID-19. EVs may provide targeted delivery of protease inhibitors, with fewer systemic side effects. More importantly, EVs are eligible for major aseptic processing and can be upscaled for mass production. Currently, the FDA is facilitating applications to treat COVID-19, which provides a very good chance to use EVs to contribute in this combat.<\/jats:p>","DOI":"10.3390\/v12050486","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T05:05:32Z","timestamp":1588050332000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for Potential Therapy of COVID-19"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7846-5674","authenticated-orcid":false,"given":"Santosh","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-9399","authenticated-orcid":false,"given":"Kaining","family":"Zhi","sequence":"additional","affiliation":[{"name":"Plough Center for Sterile Drug Delivery Solutions, University of Tennessee Health Science Center, 208 South Dudley Street, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahona","family":"Mukherji","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2874-447X","authenticated-orcid":false,"given":"Kelli","family":"Gerth","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Ave, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105924","DOI":"10.1016\/j.ijantimicag.2020.105924","article-title":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges","volume":"55","author":"Lai","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xia, S., Lan, Q., Pu, J., Wang, C., Liu, Z., Xu, W., Wang, Q., Liu, H., Jiang, S., and Lu, L. (2019). Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4. Viruses, 11.","DOI":"10.3390\/v11010056"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e01387","DOI":"10.1128\/JVI.01387-19","article-title":"Molecular Basis of Binding between Middle East Respiratory Syndrome Coronavirus and CD26 from Seven Bat Species","volume":"94","author":"Yuan","year":"2020","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102434","DOI":"10.1016\/j.jaut.2020.102434","article-title":"The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China","volume":"109","author":"Yang","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_7","first-page":"11","article-title":"The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak\u2014An update on the status","volume":"7","author":"Guo","year":"2020","journal-title":"Mil. Med Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Banerjee, A., Pasea, L., Harris, S., Gonzalez-Izquierdo, A., Torralbo, A., Shallcross, L., Noursadeghi, M., Pillay, D., Pagel, C., and Wong, W.K. (2020). Estimating excess 1- year mortality from COVID-19 according to underlying conditions and age in England: A rapid analysis using NHS health records in 3.8 million adults. medRxiv.","DOI":"10.1101\/2020.03.22.20040287"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.5582\/bst.2020.01047","article-title":"Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies","volume":"14","author":"Gao","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gautret, P., Lagier, J.C., Parola, P., Hoang, V.T., Meddeb, L., Mailhe, M., Doudier, B., Courjon, J., Giordanengo, V., and Vieira, V.E. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents, 105949. in press.","DOI":"10.1101\/2020.03.16.20037135"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S1473-3099(20)30132-8","article-title":"COVID-19: Combining antiviral and anti-inflammatory treatments","volume":"20","author":"Stebbing","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Herst, C., Burkholz, S., Sidney, J., Sette, A., Harris, P., Massey, S., Brasel, T., Cunha-Neto, E., Rosa, D., and Chao, W. (2020). An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors\u2019 CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design. bioRxiv.","DOI":"10.1101\/2020.02.25.963546"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yamey, G., Sch\u00e4ferhoff, M., Hatchett, R., Pate, M., Zhao, F., and McDade, K.K. (2020). Ensuring global access to COVID-19 vaccines. Lancet.","DOI":"10.1016\/S0140-6736(20)30763-7"},{"key":"ref_14","unstructured":"World Health Organization (2020). Considerations for Quarantine of Individuals in the Context of Containment for Coronavirus Disease (COVID-19): Interim Guidance, 19 March 2020, World Health Organization."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jin, Y., Yang, H., Ji, W., Wu, W., Chen, S., Zhang, W., and Duan, G. (2020). Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses, 12.","DOI":"10.3390\/v12040372"},{"key":"ref_16","unstructured":"(2020, April 04). How to Protect Yourself & Others, Available online: https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/prevent-getting-sick\/prevention.html."},{"key":"ref_17","unstructured":"(2020, April 04). World Health Organization, Coronavirus Disease 2019 (COVID-19): Situation Report, 67. Available online: https:\/\/reliefweb.int\/report\/world\/coronavirus-disease-2019-covid-19-situation-report-67-27-march-2020."},{"key":"ref_18","unstructured":"(2020, April 04). Situation Update Worldwide, as of 4 April 2020. Available online: https:\/\/www.ecdc.europa.eu\/en\/geographical-distribution-2019-ncov-cases."},{"key":"ref_19","unstructured":"Center, C.R. (2020, April 04). Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available online: https:\/\/coronavirus.jhu.edu\/map.html."},{"key":"ref_20","unstructured":"(2020, April 04). COVID-19 Projections Assuming Full Social Distancing through May 2020. Available online: https:\/\/covid19.healthdata.org\/projections."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, R., Pei, S., Chen, B., Song, Y., Zhang, T., Yang, W., and Shaman, J. (2020). Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science.","DOI":"10.1101\/2020.02.14.20023127"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Salath\u00e9, M., Althaus, C.L., Neher, R., Stringhini, S., Hodcroft, E., Fellay, J., Zwahlen, M., Senti, G., Battegay, M., and Wilder-Smith, A. (2020). COVID-19 epidemic in Switzerland: On the importance of testing, contact tracing and isolation. Swiss Med Wkly., 150.","DOI":"10.4414\/smw.2020.20225"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rademaker, M., Baker, C., Foley, P., Sullivan, J., and Wang, C. (2020). Advice regarding COVID-19 and use of immunomodulators, in patients with severe dermatological diseases. Australas. J. Dermatol.","DOI":"10.1111\/ajd.13295"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"South, A.M., Diz, D., and Chappell, M.C. (2020). COVID-19, ACE2 and the Cardiovascular Consequences. Am. J. Physiol. -Heart Circ. Physiol.","DOI":"10.1152\/ajpheart.00217.2020"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41569-020-0368-x","article-title":"Interaction between RAAS inhibitors and ACE2 in the context of COVID-19","volume":"17","author":"Mourad","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chowdhury, R., and Maranas, C.D. (2020). Biophysical characterization of the SARS-CoV2 spike protein binding with the ACE2 receptor explains increased COVID-19 pathogenesis. bioRxiv.","DOI":"10.1101\/2020.03.30.015891"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, Y., Chan, W., Wang, Z., Hur, J., Xie, J., Yu, H., and He, Y. (2020). Ontological and Bioinformatic Analysis of Anti-Coronavirus Drugs and Their Implication for Drug Repurposing against COVID-19. Preprints.","DOI":"10.20944\/preprints202003.0413.v1"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chen, H., Zhang, Z., Wang, L., Huang, Z., Gong, F., Li, X., Chen, Y., and WU, J.J. (2020). First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients. medRxiv.","DOI":"10.1101\/2020.03.22.20034041"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chien, M., Anderson, T.K., Jockusch, S., Tao, C., Kumar, S., Li, X., Russo, J.J., Kirchdoerfer, R.N., and Ju, J. (2020). Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase. bioRxiv.","DOI":"10.1101\/2020.03.18.997585"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.5582\/ddt.2020.01012","article-title":"Discovering drugs to treat coronavirus disease 2019 (COVID-19)","volume":"14","author":"Dong","year":"2020","journal-title":"Drug Discov. Ther."},{"key":"ref_31","unstructured":"(2020, April 04). Rolling Updates on Coronavirus Disease (COVID-19). Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/events-as-they-happen."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, C., Qi, F., Shi, K., Li, Y., Li, J., Chen, Y., Pan, J., Zhou, T., Lin, X., and Zhang, J. (2020). Thalidomide Combined with Low-Dose Glucocorticoid in the Treatment of COVID-19 pneumonia. Preprints.","DOI":"10.1002\/ctm2.35"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1016\/S0140-6736(20)30304-4","article-title":"Baricitinib as potential treatment for 2019-nCoV acute respiratory disease","volume":"395","author":"Richardson","year":"2020","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., Wang, F., Li, D., Yang, M., and Xing, L. (2020). Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA.","DOI":"10.1001\/jama.2020.4783"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/S1473-3099(20)30141-9","article-title":"Convalescent plasma as a potential therapy for COVID-19","volume":"20","author":"Chen","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., and Li, X. (2020). Effective treatment of severe COVID-19 patients with Tocilizumab. Chinaxiv Prepr.","DOI":"10.1073\/pnas.2005615117"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1074\/jbc.AC120.013056","article-title":"The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_38","first-page":"1","article-title":"Role of GS-5734 (Remdesivir) in inhibiting SARS-CoV and MERS-CoV: The expected role of GS-5734 (Remdesivir) in COVID-19 (2019-nCoV)-VYTR hypothesis","volume":"11","author":"Yethindra","year":"2020","journal-title":"Int. J. Res. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1056\/NEJMoa2001191","article-title":"First Case of 2019 Novel Coronavirus in the United States","volume":"382","author":"Holshue","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_40","unstructured":"Lu, H. (2020, April 04). Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV (HC-nCoV); Shanghai Public Health Clinical Center; ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"26833","DOI":"10.1074\/jbc.272.43.26833","article-title":"Chloroquine extends the lifetime of the activated insulin receptor complex in endosomes","volume":"272","author":"Bevan","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cortegiani, A., Ingoglia, G., Ippolito, M., Giarratano, A., and Einav, S. (2020). A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J. Crit. Care.","DOI":"10.1016\/j.jcrc.2020.03.005"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: Consider cytokine storm syndromes and immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nrmicro.2016.81","article-title":"SARS and MERS: Recent insights into emerging coronaviruses","volume":"14","author":"Falzarano","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.antiviral.2017.12.015","article-title":"Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes","volume":"150","author":"Lin","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_46","unstructured":"(2020, April 04). Studies|Covid-19|Lopinavir Ritonavir, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., and Wei, M. (2020). A Trial of Lopinavir\u2013Ritonavir in Adults Hospitalized with Severe Covid-19. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa2001282"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Martinez, M.A. (2020). Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob. Agents Chemother.","DOI":"10.1128\/AAC.00399-20"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bhatnagar, T., Murhekar, M.V., Soneja, M., Gupta, N., Giri, S., Wig, N., and Gangakhedkar, R. (2020). Lopinavir\/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: Protocol for restricted public health emergency use. Indian J. Med. Res.","DOI":"10.4103\/ijmr.IJMR_502_20"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e79","DOI":"10.3346\/jkms.2020.35.e79","article-title":"Letter to the Editor: Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: The Application of Lopinavir\/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR","volume":"35","author":"Kim","year":"2020","journal-title":"J. Korean Med. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kim, S., Kim, D.M., and Lee, B. (2020). Insufficient Sensitivity of RNA Dependent RNA Polymerase Gene of SARS-CoV-2 Viral Genome as Confirmatory Test Using Korean COVID-19 Cases. Preprints.","DOI":"10.20944\/preprints202002.0424.v1"},{"key":"ref_52","first-page":"410","article-title":"Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis","volume":"19","author":"Ortega","year":"2020","journal-title":"Excli J."},{"key":"ref_53","first-page":"400","article-title":"Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target","volume":"19","author":"Ortega","year":"2020","journal-title":"EXCLI J."},{"key":"ref_54","first-page":"95","article-title":"HIV protease inhibitors: A review of molecular selectivity and toxicity","volume":"7","author":"Lv","year":"2015","journal-title":"HIV\/AIDS"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1093\/cid\/civ1213","article-title":"Evaluation of Drug-Drug Interactions between Hepatitis C Antiviral Agents Ombitasvir, Paritaprevir\/Ritonavir, and Dasabuvir and HIV-1 Protease Inhibitors","volume":"62","author":"Khatri","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s40262-013-0056-7","article-title":"Prediction of drug-drug Interactions Between Various Antidepressants and Efavirenz or Boosted Protease Inhibitors Using a Physiologically Based Pharmacokinetic Modelling Approach","volume":"52","author":"Siccardi","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/01.qai.0000155203.89350.85","article-title":"Increased Dose of Lopinavir\/Ritonavir Compensates for Efavirenz-Induced Drug-Drug Interaction in HIV-1-Infected Children","volume":"39","author":"Bergshoeff","year":"2005","journal-title":"Jaids J. Acquir. Immune Defic. Syndr."},{"key":"ref_58","first-page":"1272","article-title":"Neutrophil Membrane-Derived Nanovesicles Alleviate Inflammation To Protect Mouse Brain Injury from Ischemic Stroke","volume":"13","author":"Dong","year":"2019","journal-title":"ACS Nano"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/gt.2017.8","article-title":"Extracellular vesicles for nucleic acid delivery: Progress and prospects for safe RNA-based gene therapy","volume":"24","author":"Jiang","year":"2017","journal-title":"Gene Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12987-018-0104-7","article-title":"Extracellular vesicles: Mediators and biomarkers of pathology along CNS barriers","volume":"15","author":"Ramirez","year":"2018","journal-title":"Fluids Barriers CNS"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.molmed.2014.03.002","article-title":"Extracellular vesicles: Emerging targets for cancer therapy","volume":"20","author":"Vader","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.2174\/138161282131151013190112","article-title":"Exosomes: Natural carriers for siRNA delivery","volume":"21","author":"Kumar","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/j.jprot.2010.06.006","article-title":"Exosomes: Extracellular organelles important in intercellular communication","volume":"73","author":"Mathivanan","year":"2010","journal-title":"J. Proteom."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.addr.2016.02.006","article-title":"Extracellular vesicles for drug delivery","volume":"106","author":"Vader","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_65","unstructured":"Tarasov, V.V., Svistunov, A.A., Chubarev, V.N., Dostdar, S.A., Sokolov, A.V., Brzecka, A., Sukocheva, O., Neganova, M.E., Klochkov, S.G., and Somasundaram, S.G. (2019). Extracellular vesicles in cancer nanomedicine. Semin. Cancer Biol., in press."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.nano.2015.10.012","article-title":"Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells","volume":"12","author":"Kim","year":"2016","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: Exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0022-1759(02)00330-7","article-title":"Production and characterization of clinical grade exosomes derived from dendritic cells","volume":"270","author":"Lamparski","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/ten.teb.2014.0300","article-title":"Emerging Roles for Extracellular Vesicles in Tissue Engineering and Regenerative Medicine","volume":"21","author":"Lamichhane","year":"2014","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1021\/acs.molpharmaceut.5b00364","article-title":"Exogenous DNA Loading into Extracellular Vesicles via Electroporation is Size-Dependent and Enables Limited Gene Delivery","volume":"12","author":"Lamichhane","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jconrel.2014.11.029","article-title":"Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins","volume":"205","author":"Fuhrmann","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.febslet.2015.04.036","article-title":"Mechanisms of RNA loading into exosomes","volume":"589","author":"Janas","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jconrel.2015.03.033","article-title":"Exosomes as drug delivery vehicles for Parkinson\u2019s disease therapy","volume":"207","author":"Haney","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"12727","DOI":"10.1038\/ncomms12727","article-title":"Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria","volume":"7","author":"Mantel","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"26316","DOI":"10.3402\/jev.v4.26316","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"4","author":"Wiklander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.nano.2014.11.009","article-title":"Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting","volume":"11","author":"Silva","year":"2015","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13045-015-0220-7","article-title":"Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma","volume":"8","author":"Lou","year":"2015","journal-title":"J. Hematol. Oncol."},{"key":"ref_78","first-page":"32274","article-title":"miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity","volume":"6","author":"Lowry","year":"2015","journal-title":"Oncotarget"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.bbrc.2014.02.007","article-title":"Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration","volume":"445","author":"Shimbo","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.1021\/acs.jmedchem.5b01697","article-title":"Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV\/AIDS","volume":"59","author":"Ghosh","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1097\/QAI.0000000000001820","article-title":"Protease Inhibitors or NNRTIs as First-Line HIV-1 Treatment in West Africa (PIONA): A Randomized Controlled Trial","volume":"79","author":"Jespersen","year":"2018","journal-title":"JAIDS J. Acquir. Immune Defic. Syndr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.diabres.2016.03.012","article-title":"Increased risk of dysglycaemia in South Africans with HIV; especially those on protease inhibitors","volume":"119","author":"Levitt","year":"2016","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_83","first-page":"29","article-title":"Efficacy of dual therapy with protease inhibitors plus lamivudine as maintenance treatment in HIV-positive patients on second line in Africa: The ANRS 12286\/MOBIDIP trial 96-week results","volume":"20","author":"Ciaffi","year":"2017","journal-title":"J. Int. Aids Soc."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Harcourt, J., Tamin, A., Lu, X., Kamili, S., Sakthivel, S.K., Wang, L., Murray, J., Queen, K., Lynch, B., and Whitaker, B. (2020). Isolation and characterization of SARS-CoV-2 from the first US COVID-19 patient. bioRxiv.","DOI":"10.1101\/2020.03.02.972935"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.actbio.2019.05.054","article-title":"Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery","volume":"94","author":"Rayamajhi","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.tcb.2016.11.003","article-title":"Extracellular Vesicles: Unique Intercellular Delivery Vehicles","volume":"27","author":"Maas","year":"2017","journal-title":"Trends Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8095","DOI":"10.2147\/IJN.S179380","article-title":"Exosome-encapsulated antibiotic against intracellular infections of methicillin-resistant Staphylococcus aureus","volume":"13","author":"Yang","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ejpb.2019.11.010","article-title":"Hot EVs\u2014How temperature affects extracellular vesicles","volume":"146","author":"Schulz","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_89","unstructured":"Liberti, L., Breckenridge, A., Hoekman, J., Leufkens, H., Lumpkin, M., McAuslane, N., Stolk, P., Zhi, K., and R\u00e4go, L. (2016, January 28). Practical aspects of developing, implementing and using facilitated regulatory pathways in the emerging markets. Proceedings of the Poster Drug Information Association Annual Meeting, Philadelphia, PA, USA."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1057\/jphp.2016.8","article-title":"Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities","volume":"37","author":"Liberti","year":"2016","journal-title":"J. Public Health Policy"},{"key":"ref_91","unstructured":"(2020, April 14). Avestin EmulsiFlex-C500 & Emulsiflex-C1000. Available online: https:\/\/www.avestin.com\/emulsiflex-c1000.htm."},{"key":"ref_92","unstructured":"(2020, April 14). Microfluidizer\u00ae Production Scale M700 Series Microfluidizers\u00ae. Available online: https:\/\/www.microfluidics-mpt.com\/microfluidizers\/m700."},{"key":"ref_93","unstructured":"Beckman-Coulter (2020, April 14). Optima XPN. Available online: https:\/\/www.beckman.com\/centrifuges\/ultracentrifuges\/optima-xpn."},{"key":"ref_94","unstructured":"Plough-Center (2020, April 14). UTHSC Plough Center for Sterile Drug Solutions. Available online: https:\/\/www.uthsc.edu\/plough-center\/."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.addr.2018.06.017","article-title":"Strategic design of extracellular vesicle drug delivery systems","volume":"130","author":"Armstrong","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jconrel.2019.06.006","article-title":"Systematic review of targeted extracellular vesicles for drug delivery\u2014Considerations on methodological and biological heterogeneity","volume":"306","author":"Gudbergsson","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/immu.200310028","article-title":"Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59","volume":"33","author":"Clayton","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/nprot.2012.131","article-title":"Exosome-mediated delivery of siRNA in vitro and in vivo","volume":"7","author":"Lee","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nbt.1807","article-title":"Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes","volume":"29","author":"Seow","year":"2011","journal-title":"Nat. Biotechnol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/5\/486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:23:54Z","timestamp":1760361834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/5\/486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,26]]},"references-count":99,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["v12050486"],"URL":"https:\/\/doi.org\/10.3390\/v12050486","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,26]]}}}