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Reperfusion therapy is vital to patient survival after a heart attack but can cause myocardial ischemia\/reperfusion injury (MI\/RI). Nitric oxide (NO) can ameliorate MI\/RI and is a key molecule for drug development. However, reactive oxygen species (ROS) can easily oxidize NO to peroxynitrite, which causes secondary cardiomyocyte damage. Herein, L\u2010arginine\u2010loaded selenium\u2010coated gold nanocages (AAS) are designed, synthesized, and modified with PCM (WLSEAGPVVTVRALRGTGSW) to obtain AASP, which targets cardiomyocytes, exhibits increased cellular uptake, and improves photoacoustic imaging in vitro and in vivo. AASP significantly inhibits oxygen glucose deprivation\/reoxygenation (OGD\/R)\u2010induced H9C2 cell cytotoxicity and apoptosis. Mechanistic investigation revealed that AASP improves mitochondrial membrane potential (MMP), restores ATP synthase activity, blocks ROS generation, and prevents NO oxidation, and NO blocks ROS release by regulating the closing of the mitochondrial permeability transition pore (mPTP). AASP administration in vivo improves myocardial function, inhibits myocardial apoptosis and fibrosis, and ultimately attenuates MI\/RI in rats by maintaining mitochondrial function and regulating NO signaling. AASP shows good safety and biocompatibility in vivo. This findings confirm the rational design of AASP, which can provide effective treatment for MI\/RI.<\/jats:p>","DOI":"10.1002\/advs.202302123","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T04:04:49Z","timestamp":1689307489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["L\u2010Arginine\u2010Loaded Gold Nanocages Ameliorate Myocardial Ischemia\/Reperfusion Injury by Promoting Nitric Oxide Production and Maintaining Mitochondrial Function"],"prefix":"10.1002","volume":"10","author":[{"given":"Zekun","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Sciences Anhui Agricultural University  Hefei Anhui 230036 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Bioscience and Technology Weifang Key Laboratory of Animal Model Research on Cardiovascular and Cerebrovascular Diseases Weifang Medical University  Weifang 261053 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital Shandong First Medical University &amp; 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Shandong Academy of Medical Sciences  Taian Shandong 271000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4473-6936","authenticated-orcid":false,"given":"Lemin","family":"Zheng","sequence":"additional","affiliation":[{"name":"The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors Research Health Science Center Peking University  Beijing 100191 China"},{"name":"Department of Neurology China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital Capital Medical University  Beijing 100070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12748-8"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306838"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201803567"},{"key":"e_1_2_8_2_3","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202004307"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00022.2018"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.982777"},{"key":"e_1_2_8_3_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02416-0"},{"key":"e_1_2_8_3_4","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0086-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz5380"},{"key":"e_1_2_8_4_2","first-page":"12","volume":"6","author":"Park B. 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