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However, the lack of safe and efficient in vivo delivery of siRNAs is a major challenge for broadening its clinical applications. Small extracellular vesicles (sEVs) are a promising delivery system for siRNAs but have limited cell\/tissue\u2010specific targeting ability. In this study, a new generation of heart\u2010targeting sEVs (CEVs) has been developed by conjugating cardiac\u2010targeting peptide (CTP) to human peripheral blood\u2010derived sEVs (PB\u2010EVs), using a simple, rapid and scalable method based on bio\u2010orthogonal copper\u2010free click chemistry. The experimental results show that CEVs have typical sEVs properties and excellent heart\u2010targeting ability. Furthermore, to treat cardiac hypertrophy, CEVs are loaded with NADPH Oxidase 4 (NOX4) siRNA (siNOX4). Consequently, CEVs@siNOX4 treatment enhances the in vitro anti\u2010hypertrophic effects by CEVs with siRNA protection and heart\u2010targeting ability. In addition, the intravenous injection of CEVs@siNOX4 into angiotensin II (Ang II)\u2010treated mice significantly improves cardiac function and reduces fibrosis and cardiomyocyte cross\u2010sectional area, with limited side effects. In conclusion, the utilization of CEVs represents an efficient strategy for heart\u2010targeted delivery of therapeutic siRNAs and holds great promise for the treatment of cardiac hypertrophy.<\/jats:p>","DOI":"10.1002\/jev2.12371","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T15:59:02Z","timestamp":1696521542000},"source":"Crossref","is-referenced-by-count":64,"title":["Engineered small extracellular vesicle\u2011mediated NOX4 siRNA delivery for targeted therapy of cardiac hypertrophy"],"prefix":"10.1002","volume":"12","author":[{"given":"Ji\u2010Young","family":"Kang","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dasom","family":"Mun","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumin","family":"Chun","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da\u2010Seul","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuri","family":"Yun","sequence":"additional","affiliation":[{"name":"GNTPharma Science and Technology Center for Health, Giheung\u2010gu Yongin\u2010si Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-7225","authenticated-orcid":false,"given":"Boyoung","family":"Joung","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"},{"name":"Graduate School of Medical Science, Brain Korea 21 Project Yonsei University College of Medicine Seodaemun\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1807"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.6b07607"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.05.011"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aab3665"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1180"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707090104"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31044"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-101512-122326"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99941"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq357"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000077012.11088.BC"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2012.08.008"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000120390.68287.BB"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116903"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.2009.00694.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.70448"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2003.08.002"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra072139"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.v32.i1.30"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hroo.2020.05.002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat3765"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20191077"},{"issue":"6","key":"e_1_2_8_24_1","first-page":"2319","article-title":"Human peripheral bloodderived exosomes for microRNA delivery","volume":"43","author":"Kang J. 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