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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2021.691548</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Therapeutic Exosomes in Prognosis and Developments of Coronary Artery Disease</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Chen</surname> <given-names>Ai-Qun</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1294672/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Gao</surname> <given-names>Xiao-Fei</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1203663/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Wang</surname> <given-names>Zhi-Mei</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1166139/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Wang</surname> <given-names>Feng</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Luo</surname> <given-names>Shuai</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Gu</surname> <given-names>Yue</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Zhang</surname> <given-names>Jun-Jie</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Chen</surname> <given-names>Shao-Liang</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="c002"><sup>&#x0002A;</sup></xref>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Department of Cardiology, Nanjing First Hospital, Nanjing Medical University</institution>, <addr-line>Nanjing</addr-line>, <country>China</country></aff>
<aff id="aff2"><sup>2</sup><institution>Department of Cardiology, Nanjing Heart Centre</institution>, <addr-line>Nanjing</addr-line>, <country>China</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Junjie Yang, University of Alabama at Birmingham, United States</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Chaoshan Han, University of Alabama at Birmingham, United States; Na Xu, Heart Institute, Cincinnati Children&#x00027;s Hospital Medical Center, United States</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Jun-Jie Zhang <email>jameszll&#x00040;163.com</email></corresp>
<corresp id="c002">Shao-Liang Chen <email>chmengx&#x00040;126.com</email></corresp>
<fn fn-type="other" id="fn001"><p>This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine</p></fn></author-notes>
<pub-date pub-type="epub">
<day>31</day>
<month>05</month>
<year>2021</year>
</pub-date>
<pub-date pub-type="collection">
<year>2021</year>
</pub-date>
<volume>8</volume>
<elocation-id>691548</elocation-id>
<history>
<date date-type="received">
<day>06</day>
<month>04</month>
<year>2021</year>
</date>
<date date-type="accepted">
<day>11</day>
<month>05</month>
<year>2021</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2021 Chen, Gao, Wang, Wang, Luo, Gu, Zhang and Chen.</copyright-statement>
<copyright-year>2021</copyright-year>
<copyright-holder>Chen, Gao, Wang, Wang, Luo, Gu, Zhang and Chen</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license> </permissions>
<abstract><p>Exosomes, with an diameter of 30&#x0007E;150 nm, could be released from almost all types of cells, which contain diverse effective constituent, such as RNAs, proteins, lipids, and so on. In recent years, exosomes have been verified to play an important role in mechanism, diagnosis, treatment, and prognosis of cardiovascular disease, especially coronary artery disease (CAD). Moreover, it has also been shown that exosomes derived from different cell types have various biological functions based on the cell stimulation and microenvironment. However, therapeutic exosomes are currently far away from clinical translation, despite it is full of hope. In this review, we summarize an update of the recent studies and systematic knowledge of therapeutic exosomes in atherosclerosis, myocardial infarction, and in-stent restenosis, which might provide a novel insight into the treatment of CAD and promote the potential clinical application of therapeutic exosomes.</p></abstract>
<kwd-group>
<kwd>exosomes</kwd>
<kwd>CAD</kwd>
<kwd>atherosclerosis</kwd>
<kwd>myocardial infarction</kwd>
<kwd>drug delivery</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="1"/>
<equation-count count="0"/>
<ref-count count="72"/>
<page-count count="7"/>
<word-count count="5027"/>
</counts>
</article-meta>
</front>
<body>

<sec sec-type="intro" id="s1">
<title>Introduction</title>
<p>Coronary artery disease (CAD) still remains a high-prevalence, high-risk, and high-fatality cardiovascular disease worldwide. In spite of the profound development of device and agents in CAD treatment, the prognosis of CAD, especially acute myocardial infarction, is far from being satisfactory (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>). Recently, exosome emerges as a novel, full of hope, and potential alternative to cell-based therapies of CAD due to its cardioprotective properties (<xref ref-type="bibr" rid="B3">3</xref>).</p>
<p>Exosomes, with diameter of 30&#x0007E;150 nm and density of 1.13&#x0007E;1.19 g/ml, are the smallest extracellular vesicles (EVs) (<xref ref-type="bibr" rid="B4">4</xref>), with a bilayer membrane structure released by almost all types of cells (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B6">6</xref>). The biogenesis of exosomes triggers from membrane proteins being endocytosed via inward budding of the cell membrane, which are then transferred to early endosomes (EEs). Afterwards, the EEs mature into multivesicle bodies (MVBs), filled with numerous intraluminal vesicles (ILVs) (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B8">8</xref>), which incorporate proteins, lipids, and genetic material during invagination (<xref ref-type="bibr" rid="B9">9</xref>). Finally, MVBs can fuse with cell membrane and release ILVs to the extracellular space (<xref ref-type="bibr" rid="B10">10</xref>), as we call them exosomes, or result in degradation via fusing with lysosomes (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B11">11</xref>).</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>The biogenesis, formation, and content of exosomes. The formation of exosomes begins with invagination of the plasma membrane, and then forms early exosomes, which form multiple vesicles after fusion, and finally release the exosomes out of the cell. During the formation of exosomes, it will actively or passively carry exogenous or endogenous cargoes. The picture on the right shows the membrane structure of exosomes, the contents of exosomes, including proteins, DNA, RNA, and others.</p></caption>
<graphic xlink:href="fcvm-08-691548-g0001.tif"/>
</fig>
<p>However, therapeutic exosomes are currently far away from clinical application, in spite of so many outstanding qualities of exosomes. In this review, we will summarize an update of the recent findings and systematic knowledge of therapeutic exosomes in CAD, which might provide a novel insight into the treatment of CAD and promote the potential clinical translation of therapeutic exosomes.</p>
</sec>
<sec id="s2">
<title>Exosomes and CAD</title>
<p>According to the progress of CAD, the relationships between exosomes and CAD are summarized into three parts: exosomes in the prevention of atherosclerosis, exosomes in the diagnosis and treatment of myocardial infarction, and exosomes in the development of in-stent restenosis (<xref ref-type="table" rid="T1">Table 1</xref>).</p>
<table-wrap position="float" id="T1">
<label>Table 1</label>
<caption><p>Relationship between exosomes and CAD.</p></caption>
<table frame="hsides" rules="groups">
<thead><tr>
<th valign="top" align="left"><bold>Disease</bold></th>
<th valign="top" align="left"><bold>Exosomal cargo</bold></th>
<th valign="top" align="left"><bold>Parent cells</bold></th>
<th valign="top" align="left"><bold>Recipient cells</bold></th>
<th valign="top" align="left"><bold>Target</bold></th>
<th valign="top" align="left"><bold>Biological/clinical relevance</bold></th>
<th valign="top" align="center"><bold>Reference</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">AS</td>
<td valign="top" align="left">miR-223</td>
<td valign="top" align="left">THP-1 monocyte</td>
<td valign="top" align="left">HUVEC</td>
<td valign="top" align="left">STAT-3 pathway</td>
<td valign="top" align="left">Anti-inflammation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B12">12</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">HSP27</td>
<td valign="top" align="left">THP-1 monocyte</td>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="left">NF-&#x003BA;B, IL-10</td>
<td valign="top" align="left">Anti-inflammation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B13">13</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Mitochondria</td>
<td valign="top" align="left">Monocyte</td>
<td valign="top" align="left">Endothelial cell</td>
<td valign="top" align="left">IFN, TNF</td>
<td valign="top" align="left">Anti-inflammation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B14">14</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-1</td>
<td valign="top" align="left">Hepatocyte</td>
<td valign="top" align="left">Endothelial cell</td>
<td valign="top" align="left">KLF4, NF-&#x003BA;B</td>
<td valign="top" align="left">Anti-inflammation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B15">15</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-21-3p</td>
<td valign="top" align="left">MACROPHAGE</td>
<td valign="top" align="left">VSMC</td>
<td valign="top" align="left">PTEN</td>
<td valign="top" align="left">Promote VSMC proliferation and degradation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B16">16</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="left">Gastric epithelial cell</td>
<td valign="top" align="left">Macrophage</td>
<td valign="top" align="left">CagA</td>
<td valign="top" align="left">Promote foam cell formation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B17">17</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">Sonic hedgehog</td>
<td valign="top" align="left">Adipocyte</td>
<td valign="top" align="left">HUVECs, MAECs</td>
<td valign="top" align="left">TGF-&#x003B1;, IL-1&#x003B2;, IL-6</td>
<td valign="top" align="left">Reduce plaque vulnerability</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B18">18</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">MI</td>
<td valign="top" align="left">miR-342-5p</td>
<td valign="top" align="left">Endothelials</td>
<td valign="top" align="left">CMs</td>
<td valign="top" align="left">Caspase9, Jnk2, Akt</td>
<td valign="top" align="left">Anti-apoptsis/proliferation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B19">19</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-21</td>
<td valign="top" align="left">HEK293T cell</td>
<td valign="top" align="left">CMs, HUVECs</td>
<td valign="top" align="left">PDCD4</td>
<td valign="top" align="left">Anti-apoptosis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B20">20</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-125b-5p</td>
<td valign="top" align="left">MSC</td>
<td valign="top" align="left">CMs</td>
<td valign="top" align="left">p53, BAK1</td>
<td valign="top" align="left">Anti-apoptosis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B21">21</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-210</td>
<td valign="top" align="left">EPC</td>
<td valign="top" align="left">Endothelial cell</td>
<td valign="top" align="left">Mitochondria</td>
<td valign="top" align="left">Anti-apoptosis/promote angiogenic function</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B22">22</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-24</td>
<td valign="top" align="left">Serum</td>
<td valign="top" align="left">H9c2 cell</td>
<td valign="top" align="left">Bim</td>
<td valign="top" align="left">Mediate Remote ischemic preconditioning</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B23">23</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-93-5p</td>
<td valign="top" align="left">Adipose stromal cell</td>
<td valign="top" align="left">CMs</td>
<td valign="top" align="left">Atg7, TLR4</td>
<td valign="top" align="left">Inhibit autophagy, anti-inflammatory</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B24">24</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">lncR</td>
<td valign="top" align="left">&#x02013;</td>
<td valign="top" align="left">Fibroblast, CMs</td>
<td valign="top" align="left">Neat1</td>
<td valign="top" align="left">Anti-fibrosis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B25">25</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-24</td>
<td valign="top" align="left">MSC</td>
<td valign="top" align="left">CD8&#x0002B;T</td>
<td valign="top" align="left">Bim</td>
<td valign="top" align="left">Anti-fibrosis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B26">26</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-130-3p</td>
<td valign="top" align="left">Adipocyte</td>
<td valign="top" align="left">CMs</td>
<td valign="top" align="left">AMPK&#x003B1;1/&#x003B1;2, Birc6, and Ucp3</td>
<td valign="top" align="left">Anti-apoptosis (diabetic)</td>
<td/>
</tr>
<tr>
<td/>
<td valign="top" align="left">Cytotoxic substance</td>
<td valign="top" align="left">Serum</td>
<td valign="top" align="left">HL-1 CMs</td>
<td valign="top" align="left">Compliment C4, ApoE, Apo C-IV</td>
<td valign="top" align="left">Anti-apoptosis (diabetic)</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B27">27</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">ILK</td>
<td valign="top" align="left">Progenitor</td>
<td valign="top" align="left">CMs</td>
<td valign="top" align="left">NF-&#x003BA;B</td>
<td valign="top" align="left">Enhance myocardial repair</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B28">28</xref>)</td>
</tr>
<tr>
<td valign="top" align="left">ISR</td>
<td valign="top" align="left">miR-222</td>
<td valign="top" align="left">M1-macrophages</td>
<td valign="top" align="left">VSMC</td>
<td valign="top" align="left">CDKN1B/CDKN1C</td>
<td valign="top" align="left">Promote VSMC proliferation and degradation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B29">29</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-125b</td>
<td valign="top" align="left">MSC</td>
<td valign="top" align="left">VSMC</td>
<td valign="top" align="left">Myosin-1E</td>
<td valign="top" align="left">Promote VSMC proliferation and degradation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B30">30</xref>)</td>
</tr>
<tr>
<td/>
<td valign="top" align="left">miR-21-5p</td>
<td valign="top" align="left">EPC</td>
<td valign="top" align="left">HUVEC</td>
<td valign="top" align="left">THBS1</td>
<td valign="top" align="left">Promote repair of endothelial cells</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B31">31</xref>)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>AS, atherosclerosis; MI, myocardial infraction; ISR, in stent restenosis; MSC, mesenchymal stem cell; EPC, endothelial progenitor cell; CM, cardiomyocyte; VSMC, vascular smooth muscle cell; HUVEC, human umbilical vein endothelial cell</italic>.</p>
</table-wrap-foot>
</table-wrap>
<sec>
<title>Therapeutic Exosomes in Atherosclerosis</title>
<p>A basic progress in the development of atherosclerosis is monocytes/macrophages accumulation into the vessel wall to produce pro-inflammatory cytokines (<xref ref-type="bibr" rid="B32">32</xref>). It has been reported that molecularly engineered M2 macrophage-derived exosomes (Further electroporated with hexyl 5-aminolevulinate hydrochloride) alleviated inflammation by promoting the release of anti-inflammatory cytokines (<xref ref-type="bibr" rid="B33">33</xref>). Paeonol could restrict atherosclerosis by obviously increasing miR-223 expression in exosomes from monocytes and inhibiting STAT3 pathway (<xref ref-type="bibr" rid="B34">34</xref>). Exosomes laden with heat shock protein 27 (HSP27) significantly stimulated NF-&#x003BA;B activation and IL-10 release, suggesting that exosomes could act as a vector in anti-inflammatory therapy (<xref ref-type="bibr" rid="B35">35</xref>). Mitochondria constituted a major subset of extracellular vesicles released by LPS-activated monocytes <italic>in vitro</italic>, which were associated with type I IFN and TNF signaling (<xref ref-type="bibr" rid="B36">36</xref>). Exosomes from nicotine-stimulated macrophages could promote atherosclerosis through facilitating VSMC migration and proliferation by targeting miR-21-3p/<italic>PTEN</italic> (<xref ref-type="bibr" rid="B37">37</xref>). Moreover, helicobacter pylori-infected gastric epithelial cells-derived exosomes accelerated macrophage foam cell formation and promoted atherosclerosis by CagA (<xref ref-type="bibr" rid="B38">38</xref>). Insulin resistance adipocyte-derived exosomes (IRADEs) has been reported to aggravate the plaque burden, whereas its effect could be attenuated by silencing sonic hedgehog in IRADEs (<xref ref-type="bibr" rid="B12">12</xref>). Besides, Jiang et al. (<xref ref-type="bibr" rid="B13">13</xref>) also reported that steatotic hepatocyte-derived EVs promoted endothelial inflammation by miR-1 delivery, KLF4 suppression and the NF-&#x003BA;B pathway activation. And in this instance, exosome therapy might be the reduction of negative contents in exosomes such as miR-1 instead of increasing therapeutic exosomes.</p>
</sec>
<sec>
<title>Therapeutic Exosomes in Myocardial Infarction</title>
<p>Myocardial infarction, which often results in poor clinical outcomes, still remains the lack of effective treatment, especially for those without culprit vessel revascularization (<xref ref-type="bibr" rid="B14">14</xref>). Therefore, current clinical treatments are mostly based on easinesss of symptoms rather than repairing infarcted cardiomyocyte (<xref ref-type="bibr" rid="B15">15</xref>).</p>
<p>Exosomes reveal significant anti-apoptosis of cardiomyocyte after myocardial infarction. Exercise-derived exosomal miR-342-5p inhibited cardiomyocyte apoptosis by targeting <italic>Caspase9</italic> and <italic>Jnk2</italic> after left anterior descending artery occlusion (<xref ref-type="bibr" rid="B16">16</xref>). EVs overexpressing miR-21 could dramatically reduce PDCD4 expression and alleviate myocardial apoptosis (<xref ref-type="bibr" rid="B15">15</xref>). Hypoxia-conditioned bone marrow-mesenchymal stem cells (MSCs)-derived exosomes (Hypo-Exo) could also protect cardiomyocytes from apoptosis by enrichment of miR-125b-5p and suppressing the expression of genes <italic>p53</italic> and <italic>BAK1</italic> (<xref ref-type="bibr" rid="B17">17</xref>). In addition, miR-210 in endothelial progenitor cell-derived exosomes (EPC-EXs) possessed antiapoptotic functions onto hypoxia/reoxygenation-injured human endothelial cells (<xref ref-type="bibr" rid="B18">18</xref>). Remote ischemic preconditioning-induced exosomes (RIPC-Exo) also could transfer miR-24 into myocardium to inhibit apoptosis (<xref ref-type="bibr" rid="B39">39</xref>).</p>
<p>Exosomes also provide cardioprotection by activating cell survival signals, inhibiting inflammatory factors, delaying ventricular remodeling, and reducing myocardial fibrosis after the occurrence of myocardial infarction. Exercise-derived exosome (Ex-exo) could carry miR-342-5p to promote Akt phosphorylation by targeting gene <italic>Ppmlf</italic> (<xref ref-type="bibr" rid="B16">16</xref>). MiR-93-5p in adipose stromal cell-derived exosomes (ADSC-Exo) inhibited inflammatory response and prevented myocardial infarction by targeting <italic>Atg7</italic> and <italic>TLR4</italic> (<xref ref-type="bibr" rid="B20">20</xref>). Kenneweg et al. (<xref ref-type="bibr" rid="B19">19</xref>) had reported that fibroblasts absorbed lncR-EVs and promoted myocardial fibrosis by targeting <italic>Neat1</italic>. Moreover, exosomal miR-24, derived from allogenic human umbilical MSC, could inhibit cardiac fibrosis (<xref ref-type="bibr" rid="B21">21</xref>).</p>
<p>Patients suffering from myocardial infarction often have a history of diabetes. Gan et al. (<xref ref-type="bibr" rid="B22">22</xref>) had demonstrated that the enrichment of miR-130b-3p from dysfunctional adipocyte exacerbated myocardial infarction and cardiomyocyte apoptosis. Serum-exosomes from normoglycemic rats could alleviate the death of hypoxia/reoxygenation-induced <italic>HL-1</italic> cell, however, which disappears in type-2 diabetes rat model (<xref ref-type="bibr" rid="B23">23</xref>).</p>
<p>Exosomes also can serve as an adjuvant therapy. Integrin Linked Kinase (ILK) acted as a target kinase by which progenitor cell-derived exosomes attenuated myocardial injury (<xref ref-type="bibr" rid="B24">24</xref>). Cheng et al. (<xref ref-type="bibr" rid="B25">25</xref>) have reported that miRNA in EVs contributed to early detection of CAD by means of point-of care applications.</p>
</sec>
<sec>
<title>Therapeutic Exosomes in In-stent Restenosis</title>
<p>Percutaneous coronary intervention has become a very important treatment strategy for CAD, but in-stent restenosis is blamed for the main cause of stent failure in patients with CAD (<xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B40">40</xref>). Several previous studies have shown that the risk of in-stent restenosis in CAD patients undergoing coronary stent implantation during 1 year follow-up was &#x0007E;5&#x02013;10% (<xref ref-type="bibr" rid="B27">27</xref>). The underlying mechanisms of in-stent restenosis are quite complex, and at least exosomes play a crucial role in the development of in-stent restenosis. For example, miR-222 from M1 macrophages (M1M)-derived exosomes promoted vascular smooth muscle cells (VSMCs) proliferation and migration, which resulted in restenosis (<xref ref-type="bibr" rid="B41">41</xref>). Wang et al. (<xref ref-type="bibr" rid="B42">42</xref>) reported that MSC-Exo enriched miR-125b and inhibited the proliferation and migration of VSMC by targeting myosin 1E. Moreover, EPC-Exo also were involved in the prevention of restenosis through delivering miR-21-5p and inhibiting <italic>THBS1</italic> expression (<xref ref-type="bibr" rid="B43">43</xref>). Recently, exosome-eluting stents have been proven to reduce intimal hyperplasia and accelerate re-endothelialization in the ischemic injury rat model.</p>
</sec>
</sec>
<sec id="s3">
<title>Optimized Treatment Strategy</title>
<p>Exosomes appear superiority and irreplaceable biological functions, and the clinical application of therapeutic exosomes is full of hope. In the first place, exosomes can avoid phagocytosis and bypass the engulfment by lysosomes (<xref ref-type="bibr" rid="B44">44</xref>) to exhibit a longer circulation half-life due to the protection of phospholipid bilayer membrane (<xref ref-type="bibr" rid="B28">28</xref>). Secondly, phospholipid bilayer of exosomes is also beneficial to the fusion with membrane of recipient cells (<xref ref-type="bibr" rid="B29">29</xref>). Thirdly, exosomes derived from animals or patients have the high homolog and low immune response to avoid exosomes degradation (<xref ref-type="bibr" rid="B30">30</xref>). Finally, exosomal regulation of &#x0201C;Homing&#x0201D; effect has been reported to target the cell type where exosomes were produced (<xref ref-type="bibr" rid="B31">31</xref>), which can provide a shortcut for exosomes delivery. In need of optimized treatment strategy, we summarized the latest research involved of sources, cargo loading, delivery and enrichment of therapeutic exosomes (<xref ref-type="fig" rid="F2">Figure 2</xref>).</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>The sources, cargo loading, delivery, and enrichment of therapeutic exosomes. Therapeutic exosomes originate from a variety of cells, including some derived from cardiovascular cells, stem cells, and others. Next, we introduce the method of carrying endogenous or exogenous goods. It then summarizes the optimization strategies for exosome delivery, including targeting peptides, novel exosome containers, and injection methods for exosomes. Finally, we analyze the influencing factors of the enrichment efficiency of exosomes. VSMC, vascular smooth muscle cell; MPS, mononuclear phagocyte system; CPC, cardiac progenitor cell; CDC, cardiosphere-derived cells; MSC, mesenchymal stem cell; PSC, pluripotent stem cell; Cltc, clathrin heavy chain.</p></caption>
<graphic xlink:href="fcvm-08-691548-g0002.tif"/>
</fig>
<sec>
<title>Source of Therapeutic Exosomes</title>
<p>It has been reported that the sources of CAD related therapeutic exosomes were commonly cardiovascular-derived endothelial cells, smooth muscle cells, macrophages and cardiac fibroblasts (<xref ref-type="bibr" rid="B45">45</xref>). In recent years, several studies have highlighted the value of MSC-Exo therapy in cardiac protection (<xref ref-type="bibr" rid="B46">46</xref>, <xref ref-type="bibr" rid="B47">47</xref>), and MSC could secret the highest amount of exosomes (<xref ref-type="bibr" rid="B48">48</xref>). Moreover, other studies found that circulating-Exo, adipocyte-EVs (<xref ref-type="bibr" rid="B12">12</xref>), hepatocyte-EVs (<xref ref-type="bibr" rid="B13">13</xref>), accompanied with different degrees of heterogeneity, all existed therapeutically effect upon CAD.</p>
</sec>
<sec>
<title>Loading Therapeutic Cargo in Exosomes</title>
<p>Although many therapeutic cargoes are inherent in parent cells previously, some therapeutic cargoes could only be loaded into exosomes by artificial means. Normally, cargoes could be loaded through fusion with liposomes, adsorption of molecules to the surface of exosomes and the insertion of lipids (<xref ref-type="bibr" rid="B49">49</xref>). It has been reported that a few procedures, such as incubation, electroporation (<xref ref-type="bibr" rid="B33">33</xref>), sonication (<xref ref-type="bibr" rid="B50">50</xref>), and so on (<xref ref-type="bibr" rid="B51">51</xref>), could promote cargo loading. When choosing the loading method of cargoes, we should consider the loading efficiency (<xref ref-type="bibr" rid="B52">52</xref>), and whether this loading method will change the physical and chemical characteristics of exosomes (<xref ref-type="bibr" rid="B53">53</xref>). Besides, membrane protein Lamp2a could increase the loading of miRNA into EVs (<xref ref-type="bibr" rid="B54">54</xref>). Moreover, drug-inducible dimerization (<xref ref-type="bibr" rid="B55">55</xref>), reversible light cleavable protein (<xref ref-type="bibr" rid="B56">56</xref>), and several advanced means of engineering exosomes also contribute to the loading of endogenous cargoes.</p>
</sec>
<sec>
<title>Delivery Method</title>
<p>Normally, therapeutic exosomes were injected intravenously and act on the cardiovascular diseases through the circulatory system as an essential treatment. However, most of these exosomes are taken up by liver or spleen (<xref ref-type="bibr" rid="B57">57</xref>). Loading homing peptides has become a popular way to optimize delivery of exosomes (<xref ref-type="bibr" rid="B58">58</xref>). In cardiovascular field, several homing peptides in connection with atherosclerosis (<xref ref-type="bibr" rid="B59">59</xref>, <xref ref-type="bibr" rid="B60">60</xref>), and ischemia/reperfusion&#x02013;injured cardiomyocytes (<xref ref-type="bibr" rid="B61">61</xref>) have been identified and applied in therapeutic regimen. For example, Wang et al. (<xref ref-type="bibr" rid="B62">62</xref>) have demonstrated that engineered exosomes fused with ischemic myocardium-targeting peptide (IMTP) increasingly accumulated in ischemic heart area. Furthermore, it has been reported that exosomes conjugated with cardiac homing peptide (CHP) has higher retention in infarcted heart (<xref ref-type="bibr" rid="B63">63</xref>).</p>
<p>Besides, Song et al. (<xref ref-type="bibr" rid="B15">15</xref>) have reported that localized injection of EVs attenuated the apoptosis of cardiomyocytes and endothelial cells in a preclinical myocardial infarction (MI) animal model. To reduce losses during transportation, Lv et al. (<xref ref-type="bibr" rid="B64">64</xref>) have reported that sEVs, incorporated in alginate hydrogel, act as a new regimen of therapy. An off-the-shelf therapeutic cardiac patch, composed of extracellular matrix and cardiac stromal cells (CSC), has been confirmed in the model of MI (<xref ref-type="bibr" rid="B65">65</xref>). The examples above demonstrate the superiority of local delivery of exosomes and improve the retention rate of exosomes.</p>
</sec>
<sec>
<title>Enrichment Efficiency</title>
<p>The enrichment efficiency of exosomes is affected by physical and chemical stimuli. The physical stimulation of exosomes mainly includes shear stress, osmotic stretch, PH and others (<xref ref-type="bibr" rid="B66">66</xref>). More importantly, the change of blood flow shear force, as the initiating factor of coronary artery disease, has also become a difficult problem for exosome delivery. Here, we focus on the shear stress in vessel where exosomes were regulated. While shear stress remain within 1&#x02013;70 dynes/cm<sup>2</sup> in normal blood vessels, severely narrowed blood vessels can produce over 1,000 dynes/cm<sup>2</sup> (<xref ref-type="bibr" rid="B67">67</xref>). High shear stress, occurring in atherosclerotic arteries, could accelerate the release of circulating-EVs gradually (<xref ref-type="bibr" rid="B68">68</xref>). The mechanisms of shear stress on EVs secretion relate to the response of membrane tension (<xref ref-type="bibr" rid="B69">69</xref>). Besides, calcium could enhance exosomes secretion from a microenvironment perspective (<xref ref-type="bibr" rid="B70">70</xref>), whereas arterial hypertension was also associated with the increase of shear stress from a macro perspective (<xref ref-type="bibr" rid="B71">71</xref>). Evidence proved that exercise training could increase EVs release under high shear stress, and decrease the risk of thrombosis correspond to stenotic arteries (<xref ref-type="bibr" rid="B72">72</xref>). Exosomes could also be affected by chemical trigger, including cytochalasin B and ethanol (<xref ref-type="bibr" rid="B46">46</xref>).</p>
</sec>
</sec>
<sec id="s4">
<title>Conclusion and Future Perspective</title>
<p>In recent years, the therapeutic effect of exosomes on heart diseases has been gradually discovered. We have summarized the progress in studying exosomes as drug delivery vehicles. Before entering the clinical transformation, a perfect therapeutic concept of exosomes is essential (<xref ref-type="bibr" rid="B3">3</xref>), and pioneering in the field of exosomes is tumor-related studies. We can draw on tumor-related studies to optimize treatment regimens. Certainly, CAD-targeted treatment options also need to take notice of the cardiovascular lineage specificity.</p>
<p>Exosomes, as natural drug delivery vehicles, have excellent biocompatibility and targeting properties. We have discovered the potential of exosomes in the treatment of CAD based on existing research. However, exosomes still face huge resistance in clinical transformation. Moreover, we hope that the optimization of therapeutic exosomes is getting better and enter the clinical application stage as soon as possible.</p>
</sec>
<sec id="s5">
<title>Author Contributions</title>
<p>A-QC and X-FG wrote the manuscript. Z-MW and FW prepared the figures. SL and YG prepared the table. J-JZ and S-LC provided the idea and revised the manuscript. All authors have agreed to the published version of the manuscript.</p>
</sec>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
</body>
<back>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sousa-Uva</surname> <given-names>M</given-names></name> <name><surname>Neumann</surname> <given-names>FJ</given-names></name> <name><surname>Ahlsson</surname> <given-names>A</given-names></name> <name><surname>Alfonso</surname> <given-names>F</given-names></name> <name><surname>Banning</surname> <given-names>AP</given-names></name> <name><surname>Benedetto</surname> <given-names>U</given-names></name> <etal/></person-group>. <article-title>2018 ESC/EACTS Guidelines on myocardial revascularization</article-title>. <source>Eur J Cardio Thorac Surg.</source> (<year>2019</year>) <volume>55</volume>:<fpage>4</fpage>&#x02013;<lpage>90</lpage>. <pub-id pub-id-type="doi">10.1093/ejcts/ezy289</pub-id></citation></ref>
<ref id="B2">
<label>2.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Benjamin</surname> <given-names>EJ</given-names></name> <name><surname>Muntner</surname> <given-names>P</given-names></name> <name><surname>Alonso</surname> <given-names>A</given-names></name> <name><surname>Bittencourt</surname> <given-names>MS</given-names></name> <name><surname>Callaway</surname> <given-names>CW</given-names></name> <name><surname>Carson</surname> <given-names>AP</given-names></name> <etal/></person-group>. <article-title>Heart disease and stroke statistics-2019 update: a report from the American Heart Association</article-title>. <source>Circulation.</source> (<year>2019</year>) <volume>139</volume>:<fpage>e56</fpage>&#x02013;<lpage>e528</lpage>. <pub-id pub-id-type="doi">10.1161/CIR.0000000000000659</pub-id></citation></ref>
<ref id="B3">
<label>3.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nazari-Shafti</surname> <given-names>TZ</given-names></name> <name><surname>Stamm</surname> <given-names>C</given-names></name> <name><surname>Falk</surname> <given-names>V</given-names></name> <name><surname>Emmert</surname> <given-names>MY</given-names></name></person-group>. <article-title>Exosomes for cardioprotection: are we ready for clinical translation?</article-title> <source>Eur Heart J</source>. (<year>2019</year>). <volume>40</volume>:<fpage>953</fpage>&#x02013;<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehz106</pub-id><pub-id pub-id-type="pmid">30896768</pub-id></citation></ref>
<ref id="B4">
<label>4.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shao</surname> <given-names>H</given-names></name> <name><surname>Im</surname> <given-names>H</given-names></name> <name><surname>Castro</surname> <given-names>CM</given-names></name> <name><surname>Breakefield</surname> <given-names>X</given-names></name> <name><surname>Weissleder</surname> <given-names>R</given-names></name> <name><surname>Lee</surname> <given-names>H</given-names></name></person-group>. <article-title>New technologies for analysis of extracellular vesicles</article-title>. <source>Chem Rev.</source> (<year>2018</year>) <volume>118</volume>:<fpage>1917</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1021/acs.chemrev.7b00534</pub-id><pub-id pub-id-type="pmid">29384376</pub-id></citation></ref>
<ref id="B5">
<label>5.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Th&#x000E9;ry</surname> <given-names>C</given-names></name> <name><surname>Zitvogel</surname> <given-names>L</given-names></name> <name><surname>Amigorena</surname> <given-names>S</given-names></name></person-group>. <article-title>Exosomes: composition, biogenesis and function</article-title>. <source>Nat Rev Immunol.</source> (<year>2002</year>) <volume>2</volume>:<fpage>569</fpage>&#x02013;<lpage>79</lpage>. <pub-id pub-id-type="doi">10.1038/nri855</pub-id></citation></ref>
<ref id="B6">
<label>6.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kalluri</surname> <given-names>R</given-names></name> <name><surname>LeBleu</surname> <given-names>VS</given-names></name></person-group>. <article-title>The biology, function, and biomedical applications of exosomes</article-title>. <source>Science.</source> (<year>2020</year>) <volume>367</volume>:<fpage>eaau6977</fpage>. <pub-id pub-id-type="doi">10.1126/science.aau6977</pub-id><pub-id pub-id-type="pmid">32029601</pub-id></citation></ref>
<ref id="B7">
<label>7.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>F&#x000E9;vrier</surname> <given-names>B</given-names></name> <name><surname>Raposo</surname> <given-names>G</given-names></name></person-group>. <article-title>Exosomes: endosomal-derived vesicles shipping extracellular messages</article-title>. <source>Curr Opin Cell Biol</source>. (<year>2004</year>) <volume>16</volume>:<fpage>415</fpage>&#x02013;<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1016/j.ceb.2004.06.003</pub-id><pub-id pub-id-type="pmid">15261674</pub-id></citation></ref>
<ref id="B8">
<label>8.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Merchant</surname> <given-names>ML</given-names></name> <name><surname>Rood</surname> <given-names>IM</given-names></name> <name><surname>Deegens</surname> <given-names>JKJ</given-names></name> <name><surname>Klein</surname> <given-names>JB</given-names></name></person-group>. <article-title>Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery</article-title>. <source>Nat Rev Nephrol.</source> (<year>2017</year>) <volume>13</volume>:<fpage>731</fpage>&#x02013;<lpage>49</lpage>. <pub-id pub-id-type="doi">10.1038/nrneph.2017.148</pub-id><pub-id pub-id-type="pmid">29081510</pub-id></citation></ref>
<ref id="B9">
<label>9.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>van Niel</surname> <given-names>G</given-names></name> <name><surname>D&#x00027;Angelo</surname> <given-names>G</given-names></name> <name><surname>Raposo</surname> <given-names>G</given-names></name></person-group>. <article-title>Shedding light on the cell biology of extracellular vesicles</article-title>. <source>Nat Rev Mol Cell Biol</source>. (<year>2018</year>) <volume>19</volume>:<fpage>213</fpage>&#x02013;<lpage>28</lpage>. <pub-id pub-id-type="doi">10.1038/nrm.2017.125</pub-id><pub-id pub-id-type="pmid">29339798</pub-id></citation></ref>
<ref id="B10">
<label>10.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lo Cicero</surname> <given-names>A</given-names></name> <name><surname>Stahl</surname> <given-names>PD</given-names></name> <name><surname>Raposo</surname> <given-names>G</given-names></name></person-group>. <article-title>Extracellular vesicles shuffling intercellular messages: for good or for bad</article-title>. <source>Curr Opin Cell Biol.</source> (<year>2015</year>). <volume>35</volume>:<fpage>69</fpage>&#x02013;<lpage>77</lpage>. <pub-id pub-id-type="doi">10.1016/j.ceb.2015.04.013</pub-id><pub-id pub-id-type="pmid">26001269</pub-id></citation></ref>
<ref id="B11">
<label>11.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Raiborg</surname> <given-names>C</given-names></name> <name><surname>Stenmark</surname> <given-names>H</given-names></name></person-group>. <article-title>The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins</article-title>. <source>Nature</source>. (<year>2009</year>) <volume>458</volume>:<fpage>445</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1038/nature07961</pub-id><pub-id pub-id-type="pmid">19325624</pub-id></citation></ref>
<ref id="B12">
<label>12.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>F</given-names></name> <name><surname>Chen</surname> <given-names>FF</given-names></name> <name><surname>Shang</surname> <given-names>YY</given-names></name> <name><surname>Li</surname> <given-names>Y</given-names></name> <name><surname>Wang</surname> <given-names>ZH</given-names></name> <name><surname>Han</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>Insulin resistance adipocyte-derived exosomes aggravate atherosclerosis by increasing vasa vasorum angiogenesis in diabetic ApoE(-/-) mice</article-title>. <source>Int J Cardiol</source>. (<year>2018</year>) <volume>265</volume>:<fpage>181</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1016/j.ijcard.2018.04.028</pub-id><pub-id pub-id-type="pmid">29685689</pub-id></citation></ref>
<ref id="B13">
<label>13.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Jiang</surname> <given-names>F</given-names></name> <name><surname>Chen</surname> <given-names>Q</given-names></name> <name><surname>Wang</surname> <given-names>W</given-names></name> <name><surname>Ling</surname> <given-names>Y</given-names></name> <name><surname>Yan</surname> <given-names>Y</given-names></name> <name><surname>Xia</surname> <given-names>P</given-names></name></person-group>. <article-title>Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1</article-title>. <source>J Hepatol</source>. (<year>2020</year>) <volume>72</volume>:<fpage>156</fpage>&#x02013;<lpage>66</lpage>. <pub-id pub-id-type="doi">10.1016/j.jhep.2019.09.014</pub-id><pub-id pub-id-type="pmid">31568800</pub-id></citation></ref>
<ref id="B14">
<label>14.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Rao</surname> <given-names>SV</given-names></name> <name><surname>Kaul</surname> <given-names>P</given-names></name> <name><surname>Newby</surname> <given-names>LK</given-names></name> <name><surname>Lincoff</surname> <given-names>AM</given-names></name> <name><surname>Hochman</surname> <given-names>J</given-names></name> <name><surname>Harrington</surname> <given-names>RA</given-names></name> <etal/></person-group>. <article-title>Poverty, process of care, and outcome in acute coronary syndromes</article-title>. <source>J Am Coll Cardiol.</source> (<year>2003</year>) <volume>41</volume>:<fpage>1948</fpage>&#x02013;<lpage>54</lpage>. <pub-id pub-id-type="doi">10.1016/S0735-1097(03)00402-9</pub-id><pub-id pub-id-type="pmid">12798563</pub-id></citation></ref>
<ref id="B15">
<label>15.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Song</surname> <given-names>Y</given-names></name> <name><surname>Zhang</surname> <given-names>C</given-names></name> <name><surname>Zhang</surname> <given-names>J</given-names></name> <name><surname>Jiao</surname> <given-names>Z</given-names></name> <name><surname>Dong</surname> <given-names>N</given-names></name> <name><surname>Wang</surname> <given-names>G</given-names></name> <etal/></person-group>. <article-title>Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction</article-title>. <source>Theranostics.</source> (<year>2019</year>) <volume>9</volume>:<fpage>2346</fpage>&#x02013;<lpage>60</lpage>. <pub-id pub-id-type="doi">10.7150/thno.29945</pub-id><pub-id pub-id-type="pmid">31149048</pub-id></citation></ref>
<ref id="B16">
<label>16.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hou</surname> <given-names>Z</given-names></name> <name><surname>Qin</surname> <given-names>X</given-names></name> <name><surname>Hu</surname> <given-names>Y</given-names></name> <name><surname>Zhang</surname> <given-names>X</given-names></name> <name><surname>Li</surname> <given-names>G</given-names></name> <name><surname>Wu</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Longterm exercise-derived exosomal miR-342-5p: a novel exerkine for cardioprotection</article-title>. <source>Circ Res.</source> (<year>2019</year>) <volume>124</volume>:<fpage>1386</fpage>&#x02013;<lpage>400</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.118.314635</pub-id><pub-id pub-id-type="pmid">30879399</pub-id></citation></ref>
<ref id="B17">
<label>17.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhu</surname> <given-names>LP</given-names></name> <name><surname>Tian</surname> <given-names>T</given-names></name> <name><surname>Wang</surname> <given-names>JY</given-names></name> <name><surname>He</surname> <given-names>JN</given-names></name> <name><surname>Chen</surname> <given-names>T</given-names></name> <name><surname>Pan</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction</article-title>. <source>Theranostics.</source> (<year>2018</year>) <volume>8</volume>:<fpage>6163</fpage>&#x02013;<lpage>77</lpage>. <pub-id pub-id-type="doi">10.7150/thno.28021</pub-id><pub-id pub-id-type="pmid">30613290</pub-id></citation></ref>
<ref id="B18">
<label>18.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ma</surname> <given-names>X</given-names></name> <name><surname>Wang</surname> <given-names>J</given-names></name> <name><surname>Li</surname> <given-names>J</given-names></name> <name><surname>Ma</surname> <given-names>C</given-names></name> <name><surname>Chen</surname> <given-names>S</given-names></name> <name><surname>Lei</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>Loading MiR-210 in endothelial progenitor cells derived exosomes boosts their beneficial effects on hypoxia/reoxygeneation-injured human endothelial cells via protecting mitochondrial function</article-title>. <source>Cell Physiol Biochem.</source> (<year>2018</year>) <volume>46</volume>:<fpage>664</fpage>&#x02013;<lpage>75</lpage>. <pub-id pub-id-type="doi">10.1159/000488635</pub-id><pub-id pub-id-type="pmid">29621777</pub-id></citation></ref>
<ref id="B19">
<label>19.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kenneweg</surname> <given-names>F</given-names></name> <name><surname>Bang</surname> <given-names>C</given-names></name> <name><surname>Xiao</surname> <given-names>K</given-names></name> <name><surname>Boulanger</surname> <given-names>CM</given-names></name> <name><surname>Loyer</surname> <given-names>X</given-names></name> <name><surname>Mazlan</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Long noncoding RNA-enriched vesicles secreted by hypoxic cardiomyocytes drive cardiac fibrosis</article-title>. <source>Mol Ther Nucleic Acids.</source> (<year>2019</year>) <volume>18</volume>:<fpage>363</fpage>&#x02013;<lpage>74</lpage>. <pub-id pub-id-type="doi">10.1016/j.omtn.2019.09.003</pub-id><pub-id pub-id-type="pmid">31634682</pub-id></citation></ref>
<ref id="B20">
<label>20.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>J</given-names></name> <name><surname>Jiang</surname> <given-names>M</given-names></name> <name><surname>Deng</surname> <given-names>S</given-names></name> <name><surname>Lu</surname> <given-names>J</given-names></name> <name><surname>Huang</surname> <given-names>H</given-names></name> <name><surname>Zhang</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>miR-93-5p-containing exosomes treatment attenuates acute myocardial infarction-induced myocardial damage</article-title>. <source>Mol Ther Nucleic Acids.</source> (<year>2018</year>) <volume>11</volume>:<fpage>103</fpage>&#x02013;<lpage>15</lpage>. <pub-id pub-id-type="doi">10.1016/j.omtn.2018.01.010</pub-id><pub-id pub-id-type="pmid">29858047</pub-id></citation></ref>
<ref id="B21">
<label>21.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shao</surname> <given-names>L</given-names></name> <name><surname>Zhang</surname> <given-names>Y</given-names></name> <name><surname>Pan</surname> <given-names>X</given-names></name> <name><surname>Liu</surname> <given-names>B</given-names></name> <name><surname>Liang</surname> <given-names>C</given-names></name> <name><surname>Zhang</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>Knockout of &#x003B2;-2 microglobulin enhances cardiac repair by modulating exosome imprinting and inhibiting stem cell-induced immune rejection</article-title>. <source>Cell Mol Life Sci.</source> (<year>2020</year>) <volume>77</volume>:<fpage>937</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1007/s00018-019-03220-3</pub-id><pub-id pub-id-type="pmid">31312880</pub-id></citation></ref>
<ref id="B22">
<label>22.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gan</surname> <given-names>L</given-names></name> <name><surname>Xie</surname> <given-names>D</given-names></name> <name><surname>Liu</surname> <given-names>J</given-names></name> <name><surname>Lau</surname> <given-names>WB</given-names></name> <name><surname>Christopher</surname> <given-names>TA</given-names></name> <name><surname>Lopez</surname> <given-names>B</given-names></name> <etal/></person-group>. <article-title>Small extracellular microvesicles mediated pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanisms exacerbating ischemia/reperfusion injury in diabetic mice</article-title>. <source>Circulation.</source> (<year>2020</year>) <volume>141</volume>:<fpage>968</fpage>&#x02013;<lpage>83</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.119.042640</pub-id><pub-id pub-id-type="pmid">31918577</pub-id></citation></ref>
<ref id="B23">
<label>23.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wider</surname> <given-names>J</given-names></name> <name><surname>Undyala</surname> <given-names>VVR</given-names></name> <name><surname>Whittaker</surname> <given-names>P</given-names></name> <name><surname>Woods</surname> <given-names>J</given-names></name> <name><surname>Chen</surname> <given-names>X</given-names></name> <name><surname>Przyklenk</surname> <given-names>K</given-names></name></person-group>. <article-title>Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication</article-title>. <source>Basic Res Cardiol.</source> (<year>2018</year>) <volume>113</volume>:<fpage>16</fpage>. <pub-id pub-id-type="doi">10.1007/s00395-018-0674-1</pub-id><pub-id pub-id-type="pmid">29524006</pub-id></citation></ref>
<ref id="B24">
<label>24.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yue</surname> <given-names>Y</given-names></name> <name><surname>Wang</surname> <given-names>C</given-names></name> <name><surname>Benedict</surname> <given-names>C</given-names></name> <name><surname>Huang</surname> <given-names>G</given-names></name> <name><surname>Truongcao</surname> <given-names>M</given-names></name> <name><surname>Roy</surname> <given-names>R</given-names></name> <etal/></person-group>. <article-title>Interleukin-10 deficiency alters endothelial progenitor cell-derived exosome reparative effect on myocardial repair via integrin-linked kinase enrichment</article-title>. <source>Circ Res.</source> (<year>2020</year>) <volume>126</volume>:<fpage>315</fpage>&#x02013;<lpage>29</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.119.315829</pub-id><pub-id pub-id-type="pmid">31815595</pub-id></citation></ref>
<ref id="B25">
<label>25.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname> <given-names>HL</given-names></name> <name><surname>Fu</surname> <given-names>CY</given-names></name> <name><surname>Kuo</surname> <given-names>WC</given-names></name> <name><surname>Chen</surname> <given-names>YW</given-names></name> <name><surname>Chen</surname> <given-names>YS</given-names></name> <name><surname>Lee</surname> <given-names>YM</given-names></name> <etal/></person-group>. <article-title>Detecting miRNA biomarkers from extracellular vesicles for cardiovascular disease with a microfluidic system</article-title>. <source>Lab Chip.</source> (<year>2018</year>) <volume>18</volume>:<fpage>2917</fpage>&#x02013;<lpage>25</lpage>. <pub-id pub-id-type="doi">10.1039/C8LC00386F</pub-id><pub-id pub-id-type="pmid">30118128</pub-id></citation></ref>
<ref id="B26">
<label>26.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname> <given-names>J</given-names></name> <name><surname>Gao</surname> <given-names>X</given-names></name> <name><surname>Kan</surname> <given-names>J</given-names></name> <name><surname>Ge</surname> <given-names>Z</given-names></name> <name><surname>Han</surname> <given-names>L</given-names></name> <name><surname>Lu</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE trial</article-title>. <source>J Am Coll Cardiol.</source> (<year>2018</year>) <volume>72</volume>:<fpage>3126</fpage>&#x02013;<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2018.09.013</pub-id><pub-id pub-id-type="pmid">33541535</pub-id></citation></ref>
<ref id="B27">
<label>27.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname> <given-names>XF</given-names></name> <name><surname>Kan</surname> <given-names>J</given-names></name> <name><surname>Zhang</surname> <given-names>YJ</given-names></name> <name><surname>Zhang</surname> <given-names>JJ</given-names></name> <name><surname>Tian</surname> <given-names>NL</given-names></name> <name><surname>Ye</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Comparison of one-year clinical outcomes between intravascular ultrasound-guided versus angiography-guided implantation of drug-eluting stents for left main lesions: a single-center analysis of a 1, 016-patient cohort</article-title>. <source>Patient Prefer Adherence.</source> (<year>2014</year>) <volume>8</volume>:<fpage>1299</fpage>&#x02013;<lpage>309</lpage>. <pub-id pub-id-type="doi">10.2147/PPA.S65768</pub-id><pub-id pub-id-type="pmid">25278749</pub-id></citation></ref>
<ref id="B28">
<label>28.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Saunderson</surname> <given-names>SC</given-names></name> <name><surname>Dunn</surname> <given-names>AC</given-names></name> <name><surname>Crocker</surname> <given-names>PR</given-names></name> <name><surname>McLellan</surname> <given-names>AD</given-names></name></person-group>. <article-title>CD169 mediates the capture of exosomes in spleen and lymph node</article-title>. <source>Blood.</source> (<year>2014</year>) <volume>123</volume>:<fpage>208</fpage>&#x02013;<lpage>16</lpage>. <pub-id pub-id-type="doi">10.1182/blood-2013-03-489732</pub-id><pub-id pub-id-type="pmid">24255917</pub-id></citation></ref>
<ref id="B29">
<label>29.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mathivanan</surname> <given-names>S</given-names></name> <name><surname>Ji</surname> <given-names>H</given-names></name> <name><surname>Simpson</surname> <given-names>RJ</given-names></name></person-group>. <article-title>Exosomes: extracellular organelles important in intercellular communication</article-title>. <source>J Proteomics.</source> (<year>2010</year>) <volume>73</volume>:<fpage>1907</fpage>&#x02013;<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1016/j.jprot.2010.06.006</pub-id><pub-id pub-id-type="pmid">20601276</pub-id></citation></ref>
<ref id="B30">
<label>30.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ha</surname> <given-names>D</given-names></name> <name><surname>Yang</surname> <given-names>N</given-names></name> <name><surname>Nadithe</surname> <given-names>V</given-names></name></person-group>. <article-title>Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges</article-title>. <source>Acta Pharm Sin B.</source> (<year>2016</year>) <volume>6</volume>:<fpage>287</fpage>&#x02013;<lpage>96</lpage>. <pub-id pub-id-type="doi">10.1016/j.apsb.2016.02.001</pub-id><pub-id pub-id-type="pmid">27471669</pub-id></citation></ref>
<ref id="B31">
<label>31.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Park</surname> <given-names>EJ</given-names></name> <name><surname>Prajuabjinda</surname> <given-names>O</given-names></name> <name><surname>Soe</surname> <given-names>ZY</given-names></name> <name><surname>Darkwah</surname> <given-names>S</given-names></name> <name><surname>Appiah</surname> <given-names>MG</given-names></name> <name><surname>Kawamoto</surname> <given-names>E</given-names></name> <etal/></person-group>. <article-title>Exosomal regulation of lymphocyte homing to the gut</article-title>. <source>Blood Adv.</source> (<year>2019</year>) <volume>3</volume>:<fpage>1</fpage>&#x02013;<lpage>11</lpage>. <pub-id pub-id-type="doi">10.1182/bloodadvances.2018024877</pub-id><pub-id pub-id-type="pmid">30733304</pub-id></citation></ref>
<ref id="B32">
<label>32.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Libby</surname> <given-names>P</given-names></name> <name><surname>Okamoto</surname> <given-names>Y</given-names></name> <name><surname>Rocha</surname> <given-names>VZ</given-names></name> <name><surname>Folco</surname> <given-names>E</given-names></name></person-group>. <article-title>Inflammation in atherosclerosis: transition from theory to practice</article-title>. <source>Circ J.</source> (<year>2010</year>) <volume>74</volume>:<fpage>213</fpage>&#x02013;<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1253/circj.CJ-09-0706</pub-id><pub-id pub-id-type="pmid">20065609</pub-id></citation></ref>
<ref id="B33">
<label>33.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname> <given-names>G</given-names></name> <name><surname>Zhang</surname> <given-names>J</given-names></name> <name><surname>Zhao</surname> <given-names>Q</given-names></name> <name><surname>Zhuang</surname> <given-names>W</given-names></name> <name><surname>Ding</surname> <given-names>J</given-names></name> <name><surname>Zhang</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Molecularly engineered macrophage-derived exosomes with inflammation tropism and intrinsic heme biosynthesis for atherosclerosis treatment</article-title>. <source>Angew Chem Int Ed Engl</source>. (<year>2020</year>) <volume>59</volume>:<fpage>4068</fpage>&#x02013;<lpage>74</lpage>. <pub-id pub-id-type="doi">10.1002/anie.201913700</pub-id><pub-id pub-id-type="pmid">31854064</pub-id></citation></ref>
<ref id="B34">
<label>34.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Li</surname> <given-names>C</given-names></name> <name><surname>Wu</surname> <given-names>H</given-names></name> <name><surname>Xie</surname> <given-names>X</given-names></name> <name><surname>Sun</surname> <given-names>Y</given-names></name> <name><surname>Dai</surname> <given-names>M</given-names></name></person-group>. <article-title>Paeonol attenuated inflammatory response of endothelial cells via stimulating monocytes-derived exosomal microRNA-223</article-title>. <source>Front Pharmacol</source>. (<year>2018</year>) <volume>9</volume>:<fpage>1105</fpage>. <pub-id pub-id-type="doi">10.3389/fphar.2018.01105</pub-id><pub-id pub-id-type="pmid">30515094</pub-id></citation></ref>
<ref id="B35">
<label>35.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shi</surname> <given-names>C</given-names></name> <name><surname>Ulke-Lem&#x000E9;e</surname> <given-names>A</given-names></name> <name><surname>Deng</surname> <given-names>J</given-names></name> <name><surname>Batulan</surname> <given-names>Z</given-names></name> <name><surname>O&#x00027;Brien</surname> <given-names>ER</given-names></name></person-group>. <article-title>Characterization of heat shock protein 27 in extracellular vesicles: a potential anti-inflammatory therapy</article-title>. <source>FASEB J</source>. (<year>2019</year>) <volume>33</volume>:<fpage>1617</fpage>&#x02013;<lpage>30</lpage>. <pub-id pub-id-type="doi">10.1096/fj.201800987R</pub-id><pub-id pub-id-type="pmid">30188755</pub-id></citation></ref>
<ref id="B36">
<label>36.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Puhm</surname> <given-names>F</given-names></name> <name><surname>Afonyushkin</surname> <given-names>T</given-names></name> <name><surname>Resch</surname> <given-names>U</given-names></name> <name><surname>Obermayer</surname> <given-names>G</given-names></name> <name><surname>Rohde</surname> <given-names>M</given-names></name> <name><surname>Penz</surname> <given-names>T</given-names></name> <etal/></person-group>. <article-title>Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells</article-title>. <source>Circ Res.</source> (<year>2019</year>) <volume>125</volume>:<fpage>43</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.118.314601</pub-id><pub-id pub-id-type="pmid">31647771</pub-id></citation></ref>
<ref id="B37">
<label>37.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhu</surname> <given-names>J</given-names></name> <name><surname>Liu</surname> <given-names>B</given-names></name> <name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Wang</surname> <given-names>D</given-names></name> <name><surname>Ni</surname> <given-names>H</given-names></name> <name><surname>Zhang</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation</article-title>. <source>Theranostics</source>. (<year>2019</year>) <volume>9</volume>:<fpage>6901</fpage>&#x02013;<lpage>19</lpage>. <pub-id pub-id-type="doi">10.7150/thno.37357</pub-id><pub-id pub-id-type="pmid">31660076</pub-id></citation></ref>
<ref id="B38">
<label>38.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname> <given-names>S</given-names></name> <name><surname>Xia</surname> <given-names>YP</given-names></name> <name><surname>Luo</surname> <given-names>XY</given-names></name> <name><surname>Chen</surname> <given-names>SL</given-names></name> <name><surname>Li</surname> <given-names>BW</given-names></name> <name><surname>Ye</surname> <given-names>ZM</given-names></name> <etal/></person-group>. <article-title>Exosomal CagA derived from <italic>Helicobacter pylori</italic>-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis</article-title>. <source>J Mol Cell Cardiol</source>. (<year>2019</year>) <volume>135</volume>:<fpage>40</fpage>&#x02013;<lpage>51</lpage>. <pub-id pub-id-type="doi">10.1016/j.yjmcc.2019.07.011</pub-id><pub-id pub-id-type="pmid">31352044</pub-id></citation></ref>
<ref id="B39">
<label>39.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Minghua</surname> <given-names>W</given-names></name> <name><surname>Zhijian</surname> <given-names>G</given-names></name> <name><surname>Chahua</surname> <given-names>H</given-names></name> <name><surname>Qiang</surname> <given-names>L</given-names></name> <name><surname>Minxuan</surname> <given-names>X</given-names></name> <name><surname>Luqiao</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24</article-title>. <source>Cell Death Dis.</source> (<year>2018</year>) <volume>9</volume>:<fpage>320</fpage>. <pub-id pub-id-type="doi">10.1038/s41419-018-0274-x</pub-id><pub-id pub-id-type="pmid">29476052</pub-id></citation></ref>
<ref id="B40">
<label>40.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname> <given-names>XF</given-names></name> <name><surname>Lu</surname> <given-names>S</given-names></name> <name><surname>Ge</surname> <given-names>Z</given-names></name> <name><surname>Zuo</surname> <given-names>GF</given-names></name> <name><surname>Wang</surname> <given-names>ZM</given-names></name> <name><surname>Wang</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Relationship between high platelet reactivity on clopidogrel and long-term clinical outcomes after drug-eluting stents implantation (PAINT-DES): a prospective, propensity score-matched cohort study</article-title>. <source>BMC Cardiovasc Disord.</source> (<year>2018</year>) <volume>18</volume>:<fpage>103</fpage>. <pub-id pub-id-type="doi">10.1186/s12872-018-0841-1</pub-id><pub-id pub-id-type="pmid">29793432</pub-id></citation></ref>
<ref id="B41">
<label>41.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Zhu</surname> <given-names>H</given-names></name> <name><surname>Shi</surname> <given-names>H</given-names></name> <name><surname>Zhao</surname> <given-names>H</given-names></name> <name><surname>Gao</surname> <given-names>R</given-names></name> <name><surname>Weng</surname> <given-names>X</given-names></name> <etal/></person-group>. <article-title>Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway</article-title>. <source>Cell Death Dis.</source> (<year>2019</year>) <volume>10</volume>:<fpage>422</fpage>. <pub-id pub-id-type="doi">10.1038/s41419-019-1667-1</pub-id><pub-id pub-id-type="pmid">31142732</pub-id></citation></ref>
<ref id="B42">
<label>42.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>D</given-names></name> <name><surname>Gao</surname> <given-names>B</given-names></name> <name><surname>Yue</surname> <given-names>J</given-names></name> <name><surname>Liu</surname> <given-names>F</given-names></name> <name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Fu</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>Exosomes from mesenchymal stem cells expressing miR-125b inhibit neointimal hyperplasia via myosin IE</article-title>. <source>J Cell Mol Med.</source> (<year>2019</year>) <volume>23</volume>:<fpage>1528</fpage>&#x02013;<lpage>40</lpage>. <pub-id pub-id-type="doi">10.1111/jcmm.14060</pub-id><pub-id pub-id-type="pmid">30484954</pub-id></citation></ref>
<ref id="B43">
<label>43.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hu</surname> <given-names>H</given-names></name> <name><surname>Wang</surname> <given-names>B</given-names></name> <name><surname>Jiang</surname> <given-names>C</given-names></name> <name><surname>Li</surname> <given-names>R</given-names></name> <name><surname>Zhao</surname> <given-names>J</given-names></name></person-group>. <article-title>Endothelial progenitor cell-derived exosomes facilitate vascular endothelial cell repair through shuttling miR-21-5p to modulate Thrombospondin-1 expression</article-title>. <source>Clin Sci (Lond).</source> (<year>2019</year>) <volume>133</volume>:<fpage>1629</fpage>&#x02013;<lpage>44</lpage>. <pub-id pub-id-type="doi">10.1042/CS20190188</pub-id><pub-id pub-id-type="pmid">31315970</pub-id></citation></ref>
<ref id="B44">
<label>44.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Bunggulawa</surname> <given-names>EJ</given-names></name> <name><surname>Wang</surname> <given-names>W</given-names></name> <name><surname>Yin</surname> <given-names>T</given-names></name> <name><surname>Wang</surname> <given-names>N</given-names></name> <name><surname>Durkan</surname> <given-names>C</given-names></name> <name><surname>Wang</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>Recent advancements in the use of exosomes as drug delivery systems</article-title>. <source>J Nanobiotechnol.</source> (<year>2018</year>) <volume>16</volume>:<fpage>81</fpage>. <pub-id pub-id-type="doi">10.1186/s12951-018-0403-9</pub-id><pub-id pub-id-type="pmid">30326899</pub-id></citation></ref>
<ref id="B45">
<label>45.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chistiakov</surname> <given-names>DA</given-names></name> <name><surname>Orekhov</surname> <given-names>AN</given-names></name> <name><surname>Bobryshev</surname> <given-names>YV</given-names></name></person-group>. <article-title>Cardiac extracellular vesicles in normal and infarcted heart</article-title>. <source>Int J Mol Sci.</source> (<year>2016</year>) <volume>17</volume>:<fpage>63</fpage>. <pub-id pub-id-type="doi">10.3390/ijms17010063</pub-id><pub-id pub-id-type="pmid">26742038</pub-id></citation></ref>
<ref id="B46">
<label>46.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Piffoux</surname> <given-names>M</given-names></name> <name><surname>Nicol&#x000E1;s-Boluda</surname> <given-names>A</given-names></name> <name><surname>Mulens-Arias</surname> <given-names>V</given-names></name> <name><surname>Richard</surname> <given-names>S</given-names></name> <name><surname>Rahmi</surname> <given-names>G</given-names></name> <name><surname>Gazeau</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Extracellular vesicles for personalized medicine: The input of physically triggered production, loading and theranostic properties</article-title>. <source>Adv Drug Deliv Rev.</source> (<year>2019</year>) <volume>138</volume>:<fpage>247</fpage>&#x02013;<lpage>58</lpage>. <pub-id pub-id-type="doi">10.1016/j.addr.2018.12.009</pub-id></citation></ref>
<ref id="B47">
<label>47.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Caplan</surname> <given-names>AI</given-names></name> <name><surname>Dennis</surname> <given-names>JE</given-names></name></person-group>. <article-title>Mesenchymal stem cells as trophic mediators</article-title>. <source>J Cell Biochem.</source> (<year>2006</year>) <volume>98</volume>:<fpage>1076</fpage>&#x02013;<lpage>84</lpage>. <pub-id pub-id-type="doi">10.1002/jcb.20886</pub-id><pub-id pub-id-type="pmid">24982174</pub-id></citation></ref>
<ref id="B48">
<label>48.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yeo</surname> <given-names>RW</given-names></name> <name><surname>Lai</surname> <given-names>RC</given-names></name> <name><surname>Zhang</surname> <given-names>B</given-names></name> <name><surname>Tan</surname> <given-names>SS</given-names></name> <name><surname>Yin</surname> <given-names>Y</given-names></name> <name><surname>Teh</surname> <given-names>BJ</given-names></name> <etal/></person-group>. <article-title>Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery</article-title>. <source>Adv Drug Deliv Rev.</source> (<year>2013</year>) <volume>65</volume>:<fpage>336</fpage>&#x02013;<lpage>41</lpage>. <pub-id pub-id-type="doi">10.1016/j.addr.2012.07.001</pub-id><pub-id pub-id-type="pmid">22780955</pub-id></citation></ref>
<ref id="B49">
<label>49.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Richter</surname> <given-names>M</given-names></name> <name><surname>Vader</surname> <given-names>P</given-names></name> <name><surname>Fuhrmann</surname> <given-names>G</given-names></name></person-group>. <article-title>Approaches to surface engineering of extracellular vesicles</article-title>. <source>Adv Drug Deliv Rev.</source> (<year>2021</year>) <volume>173</volume>:<fpage>416</fpage>&#x02013;<lpage>26</lpage>. <pub-id pub-id-type="doi">10.1016/j.addr.2021.03.020</pub-id><pub-id pub-id-type="pmid">33831479</pub-id></citation></ref>
<ref id="B50">
<label>50.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname> <given-names>MS</given-names></name> <name><surname>Haney</surname> <given-names>MJ</given-names></name> <name><surname>Zhao</surname> <given-names>Y</given-names></name> <name><surname>Mahajan</surname> <given-names>V</given-names></name> <name><surname>Deygen</surname> <given-names>I</given-names></name> <name><surname>Klyachko</surname> <given-names>NL</given-names></name> <etal/></person-group>. <article-title>Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells</article-title>. <source>Nanomed Nanotechnol Biol Med.</source> (<year>2016</year>) <volume>12</volume>:<fpage>655</fpage>&#x02013;<lpage>64</lpage>. <pub-id pub-id-type="doi">10.1016/j.nano.2015.10.012</pub-id><pub-id pub-id-type="pmid">26586551</pub-id></citation></ref>
<ref id="B51">
<label>51.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Haney</surname> <given-names>MJ</given-names></name> <name><surname>Klyachko</surname> <given-names>NL</given-names></name> <name><surname>Zhao</surname> <given-names>Y</given-names></name> <name><surname>Gupta</surname> <given-names>R</given-names></name> <name><surname>Plotnikova</surname> <given-names>EG</given-names></name> <name><surname>He</surname> <given-names>Z</given-names></name> <etal/></person-group>. <article-title>Exosomes as drug delivery vehicles for Parkinson&#x00027;s disease therapy</article-title>. <source>J Control Release.</source> (<year>2015</year>) <volume>207</volume>:<fpage>18</fpage>&#x02013;<lpage>30</lpage>. <pub-id pub-id-type="doi">10.1016/j.jconrel.2015.03.033</pub-id><pub-id pub-id-type="pmid">25836593</pub-id></citation></ref>
<ref id="B52">
<label>52.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Elsharkasy</surname> <given-names>OM</given-names></name> <name><surname>Nordin</surname> <given-names>JZ</given-names></name> <name><surname>Hagey</surname> <given-names>DW</given-names></name> <name><surname>de Jong</surname> <given-names>OG</given-names></name> <name><surname>Schiffelers</surname> <given-names>RM</given-names></name> <name><surname>Andaloussi</surname> <given-names>SE</given-names></name> <etal/></person-group>. <article-title>Extracellular vesicles as drug delivery systems: Why and how?</article-title> <source>Adv Drug Deliv Rev.</source> (<year>2020</year>) <volume>159</volume>:<fpage>332</fpage>&#x02013;<lpage>43</lpage>. <pub-id pub-id-type="doi">10.1016/j.addr.2020.04.004</pub-id><pub-id pub-id-type="pmid">32305351</pub-id></citation></ref>
<ref id="B53">
<label>53.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kooijmans</surname> <given-names>SAA</given-names></name> <name><surname>Stremersch</surname> <given-names>S</given-names></name> <name><surname>Braeckmans</surname> <given-names>K</given-names></name> <name><surname>de Smedt</surname> <given-names>SC</given-names></name> <name><surname>Hendrix</surname> <given-names>A</given-names></name> <name><surname>Wood</surname> <given-names>MJA</given-names></name> <etal/></person-group>. <article-title>Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles</article-title>. <source>J Control Release.</source> (<year>2013</year>) <volume>172</volume>:<fpage>229</fpage>&#x02013;<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1016/j.jconrel.2013.08.014</pub-id><pub-id pub-id-type="pmid">23994516</pub-id></citation></ref>
<ref id="B54">
<label>54.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sutaria</surname> <given-names>DS</given-names></name> <name><surname>Jiang</surname> <given-names>J</given-names></name> <name><surname>Elgamal</surname> <given-names>OA</given-names></name> <name><surname>Pomeroy</surname> <given-names>SM</given-names></name> <name><surname>Badawi</surname> <given-names>M</given-names></name> <name><surname>Zhu</surname> <given-names>X</given-names></name> <etal/></person-group>. <article-title>Low active loading of cargo into engineered extracellular vesicles results in inefficient miRNA mimic delivery</article-title>. <source>J Extracell Vesicles.</source> (<year>2017</year>) <volume>6</volume>:<fpage>1333882</fpage>. <pub-id pub-id-type="doi">10.1080/20013078.2017.1333882</pub-id><pub-id pub-id-type="pmid">28717424</pub-id></citation></ref>
<ref id="B55">
<label>55.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Banaszynski</surname> <given-names>LA</given-names></name> <name><surname>Liu</surname> <given-names>CW</given-names></name> <name><surname>Wandless</surname> <given-names>TJ</given-names></name></person-group>. <article-title>Characterization of the FKBP.rapamycin.FRB ternary complex</article-title>. <source>J Am Chem Soc.</source> (<year>2005</year>) <volume>127</volume>:<fpage>4715</fpage>&#x02013;<lpage>21</lpage>. <pub-id pub-id-type="doi">10.1021/ja043277y</pub-id><pub-id pub-id-type="pmid">15796538</pub-id></citation></ref>
<ref id="B56">
<label>56.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yim</surname> <given-names>N</given-names></name> <name><surname>Ryu</surname> <given-names>SW</given-names></name> <name><surname>Choi</surname> <given-names>K</given-names></name> <name><surname>Lee</surname> <given-names>KR</given-names></name> <name><surname>Lee</surname> <given-names>S</given-names></name> <name><surname>Choi</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module</article-title>. <source>Nat Commun.</source> (<year>2016</year>) <volume>7</volume>:<fpage>12277</fpage>. <pub-id pub-id-type="doi">10.1038/ncomms12277</pub-id><pub-id pub-id-type="pmid">27447450</pub-id></citation></ref>
<ref id="B57">
<label>57.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Armstrong</surname> <given-names>JPK</given-names></name> <name><surname>Stevens</surname> <given-names>MM</given-names></name></person-group>. <article-title>Strategic design of extracellular vesicle drug delivery systems</article-title>. <source>Adv Drug Deliv Rev.</source> (<year>2018</year>) <volume>130</volume>:<fpage>12</fpage>&#x02013;<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1016/j.addr.2018.06.017</pub-id><pub-id pub-id-type="pmid">29959959</pub-id></citation></ref>
<ref id="B58">
<label>58.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shen</surname> <given-names>B</given-names></name> <name><surname>Wu</surname> <given-names>N</given-names></name> <name><surname>Yang</surname> <given-names>JM</given-names></name> <name><surname>Gould</surname> <given-names>SJ</given-names></name></person-group>. <article-title>Protein targeting to exosomes/microvesicles by plasma membrane anchors</article-title>. <source>J Biol Chem.</source> (<year>2011</year>) <volume>286</volume>:<fpage>14383</fpage>&#x02013;<lpage>95</lpage>. <pub-id pub-id-type="doi">10.1074/jbc.M110.208660</pub-id><pub-id pub-id-type="pmid">21300796</pub-id></citation></ref>
<ref id="B59">
<label>59.</label>
<citation citation-type="journal"><person-group person-group-type="author"><collab>Hong HY Lee HY Kwak W Yoo J Na MH So IS </collab></person-group>. <article-title>Phage display selection of peptides that home toatherosclerotic plaques: IL-4 receptor as a candidate target in atherosclerosis</article-title>. <source>J Cell Mol Med.</source> (<year>2008</year>) <volume>12</volume>:<fpage>2003</fpage>&#x02013;<lpage>14</lpage>. <pub-id pub-id-type="doi">10.1111/j.1582-4934.2008.00189.x</pub-id></citation></ref>
<ref id="B60">
<label>60.</label>
<citation citation-type="journal"><person-group person-group-type="author"><collab>Lee GY Kim JH Oh GT Lee BH Kwon IC Kim IS</collab></person-group>. <article-title>Molecular targeting of atherosclerotic plaques by a stabilin-2-specific peptide ligand</article-title>. <source>J Control Release.</source> (<year>2011</year>) <volume>155</volume>:<fpage>211</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1016/j.jconrel.2011.07.010</pub-id></citation></ref>
<ref id="B61">
<label>61.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Won</surname> <given-names>YW</given-names></name> <name><surname>McGinn</surname> <given-names>AN</given-names></name> <name><surname>Lee</surname> <given-names>M</given-names></name> <name><surname>Bull</surname> <given-names>DA</given-names></name> <name><surname>Kim</surname> <given-names>SW</given-names></name></person-group>. <article-title>Targeted gene delivery to ischemic myocardium by homing peptide-guided polymeric carrier</article-title>. <source>Mol Pharm.</source> (<year>2013</year>) <volume>10</volume>:<fpage>378</fpage>&#x02013;<lpage>85</lpage>. <pub-id pub-id-type="doi">10.1021/mp300500y</pub-id><pub-id pub-id-type="pmid">23214982</pub-id></citation></ref>
<ref id="B62">
<label>62.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>X</given-names></name> <name><surname>Chen</surname> <given-names>Y</given-names></name> <name><surname>Zhao</surname> <given-names>Z</given-names></name> <name><surname>Meng</surname> <given-names>Q</given-names></name> <name><surname>Yu</surname> <given-names>Y</given-names></name> <name><surname>Sun</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction</article-title>. <source>J Am Heart Assoc.</source> (<year>2018</year>) <volume>7</volume>:<fpage>e008737</fpage>. <pub-id pub-id-type="doi">10.1161/JAHA.118.008737</pub-id><pub-id pub-id-type="pmid">30371236</pub-id></citation></ref>
<ref id="B63">
<label>63.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vandergriff</surname> <given-names>A</given-names></name> <name><surname>Huang</surname> <given-names>K</given-names></name> <name><surname>Shen</surname> <given-names>D</given-names></name> <name><surname>Hu</surname> <given-names>S</given-names></name> <name><surname>Hensley</surname> <given-names>MT</given-names></name> <name><surname>Caranasos</surname> <given-names>TG</given-names></name> <etal/></person-group>. <article-title>Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide</article-title>. <source>Theranostics.</source> (<year>2018</year>) <volume>8</volume>:<fpage>1869</fpage>&#x02013;<lpage>78</lpage>. <pub-id pub-id-type="doi">10.7150/thno.20524</pub-id><pub-id pub-id-type="pmid">29556361</pub-id></citation></ref>
<ref id="B64">
<label>64.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lv</surname> <given-names>K</given-names></name> <name><surname>Li</surname> <given-names>Q</given-names></name> <name><surname>Zhang</surname> <given-names>L</given-names></name> <name><surname>Wang</surname> <given-names>Y</given-names></name> <name><surname>Zhong</surname> <given-names>Z</given-names></name> <name><surname>Zhao</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction</article-title>. <source>Theranostics.</source> (<year>2019</year>) <volume>9</volume>:<fpage>7403</fpage>&#x02013;<lpage>16</lpage>. <pub-id pub-id-type="doi">10.7150/thno.32637</pub-id><pub-id pub-id-type="pmid">31695776</pub-id></citation></ref>
<ref id="B65">
<label>65.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname> <given-names>K</given-names></name> <name><surname>Ozpinar</surname> <given-names>EW</given-names></name> <name><surname>Su</surname> <given-names>T</given-names></name> <name><surname>Tang</surname> <given-names>J</given-names></name> <name><surname>Shen</surname> <given-names>D</given-names></name> <name><surname>Qiao</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs</article-title>. <source>Sci Transl Med.</source> (<year>2020</year>) <volume>12</volume>:<fpage>eaat9683</fpage>. <pub-id pub-id-type="doi">10.1126/scitranslmed.aat9683</pub-id><pub-id pub-id-type="pmid">32269164</pub-id></citation></ref>
<ref id="B66">
<label>66.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>H</given-names></name> <name><surname>Liu</surname> <given-names>S</given-names></name> <name><surname>Qiu</surname> <given-names>X</given-names></name> <name><surname>Yang</surname> <given-names>X</given-names></name> <name><surname>Bao</surname> <given-names>L</given-names></name> <name><surname>Pu</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells</article-title>. <source>Autophagy.</source> (<year>2020</year>) <volume>16</volume>:<fpage>2140</fpage>&#x02013;<lpage>55</lpage>. <pub-id pub-id-type="doi">10.1080/15548627.2020.1717128</pub-id><pub-id pub-id-type="pmid">31959090</pub-id></citation></ref>
<ref id="B67">
<label>67.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Korin</surname> <given-names>N</given-names></name> <name><surname>Gounis</surname> <given-names>MJ</given-names></name> <name><surname>Wakhloo</surname> <given-names>AK</given-names></name> <name><surname>Ingber</surname> <given-names>DE</given-names></name></person-group>. <article-title>Targeted drug delivery to flow-obstructed blood vessels using mechanically activated nanotherapeutics</article-title>. <source>JAMA Neurol.</source> (<year>2015</year>) <volume>72</volume>:<fpage>119</fpage>&#x02013;<lpage>22</lpage>. <pub-id pub-id-type="doi">10.1001/jamaneurol.2014.2886</pub-id><pub-id pub-id-type="pmid">25365638</pub-id></citation></ref>
<ref id="B68">
<label>68.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Miyazaki</surname> <given-names>Y</given-names></name> <name><surname>Nomura</surname> <given-names>S</given-names></name> <name><surname>Miyake</surname> <given-names>T</given-names></name> <name><surname>Kagawa</surname> <given-names>H</given-names></name> <name><surname>Kitada</surname> <given-names>C</given-names></name> <name><surname>Taniguchi</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>High shear stress can initiate both platelet aggregation and shedding of procoagulant containing microparticles</article-title>. <source>Blood.</source> (<year>1996</year>) <volume>88</volume>:<fpage>3456</fpage>&#x02013;<lpage>64</lpage>. <pub-id pub-id-type="doi">10.1182/blood.V88.9.3456.bloodjournal8893456</pub-id><pub-id pub-id-type="pmid">8896411</pub-id></citation></ref>
<ref id="B69">
<label>69.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Staykova</surname> <given-names>M</given-names></name> <name><surname>Holmes</surname> <given-names>DP</given-names></name> <name><surname>Read</surname> <given-names>C</given-names></name> <name><surname>Stone</surname> <given-names>HA</given-names></name></person-group>. <article-title>Mechanics of surface area regulation in cells examined with confined lipid membranes</article-title>. <source>Proc Natl Acad Sci U S A.</source> (<year>2011</year>) <volume>108</volume>:<fpage>9084</fpage>&#x02013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1102358108</pub-id><pub-id pub-id-type="pmid">21562210</pub-id></citation></ref>
<ref id="B70">
<label>70.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Savina</surname> <given-names>A</given-names></name> <name><surname>Fader</surname> <given-names>CM</given-names></name> <name><surname>Damiani</surname> <given-names>MT</given-names></name> <name><surname>Colombo</surname> <given-names>MI</given-names></name></person-group>. <article-title>Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner</article-title>. <source>Traffic (Copenhagen, Denmark)</source>. (<year>2005</year>) <volume>6</volume>:<fpage>131</fpage>&#x02013;<lpage>43</lpage>. <pub-id pub-id-type="doi">10.1111/j.1600-0854.2004.00257.x</pub-id><pub-id pub-id-type="pmid">15634213</pub-id></citation></ref>
<ref id="B71">
<label>71.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gatzoulis</surname> <given-names>MA</given-names></name> <name><surname>Alonso-Gonzalez</surname> <given-names>R</given-names></name> <name><surname>Beghetti</surname> <given-names>M</given-names></name></person-group>. <article-title>Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease</article-title>. <source>Eur Respir Rev.</source> (<year>2009</year>) <volume>18</volume>:<fpage>154</fpage>&#x02013;<lpage>61</lpage>. <pub-id pub-id-type="doi">10.1183/09059180.00003309</pub-id><pub-id pub-id-type="pmid">20956136</pub-id></citation></ref>
<ref id="B72">
<label>72.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname> <given-names>YW</given-names></name> <name><surname>Chen</surname> <given-names>YC</given-names></name> <name><surname>Wang</surname> <given-names>JS</given-names></name></person-group>. <article-title>Absolute hypoxic exercise training enhances <italic>in vitro</italic> thrombin generation by increasing procoagulant platelet-derived microparticles under high shear stress in sedentary men</article-title>. <source>Clin Sci (Lond).</source> (<year>2013</year>) <volume>124</volume>:<fpage>639</fpage>&#x02013;<lpage>49</lpage>. <pub-id pub-id-type="doi">10.1042/CS20120540</pub-id><pub-id pub-id-type="pmid">23252666</pub-id></citation></ref>
</ref-list>
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<fn fn-type="financial-disclosure"><p><bold>Funding.</bold> This study was funded by the National Natural Science Foundation of China (NSFC 81970307), and was jointly supported by Six Talent Peaks Project of Jiangsu Province (2019-WSN-156), Social Development Project of Jiangsu Province (BE2019615, BE2019616), Jiangsu Commission of Health (H2019077), and Nanjing Health Youth Talent Training project (QRX17017).</p>
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