{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T23:55:43Z","timestamp":1771372543907,"version":"3.50.1"},"posted":{"date-parts":[[2024,6,18]]},"group-title":"Cell Biology","reference-count":59,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acids\n                    <jats:italic>in vivo<\/jats:italic>\n                    to form self-assembled nanoparticles of \u223c55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation\/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.17.599454","type":"posted-content","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T05:55:11Z","timestamp":1718690111000},"source":"Crossref","is-referenced-by-count":3,"title":["Systemic delivery of murine SOD2 mRNA to experimental abdominal aortic aneurysm mitigates expansion and rupture"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9630-3842","authenticated-orcid":false,"given":"Huimin","family":"Yan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonina","family":"Akk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-0771","authenticated-orcid":false,"given":"Angela C.","family":"Hirbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel A.","family":"Wickline","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5921-2399","authenticated-orcid":false,"given":"Elisha D.O.","family":"Roberson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1127-3699","authenticated-orcid":false,"given":"Christine T.N.","family":"Pham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024062118401572000_2024.06.17.599454v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.690982"},{"key":"2024062118401572000_2024.06.17.599454v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2005.02157.x"},{"key":"2024062118401572000_2024.06.17.599454v1.3","doi-asserted-by":"publisher","DOI":"10.1586\/14779072.2015.1074861"},{"key":"2024062118401572000_2024.06.17.599454v1.4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8931"},{"key":"2024062118401572000_2024.06.17.599454v1.5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215334"},{"key":"2024062118401572000_2024.06.17.599454v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.305269"},{"key":"2024062118401572000_2024.06.17.599454v1.7","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1042\/CS20150547","article-title":"Oxidative stress and abdominal aortic aneurysm: potential treatment targets","volume":"130","year":"2016","journal-title":"Clin Sci (Lond)"},{"key":"2024062118401572000_2024.06.17.599454v1.8","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00224.x"},{"key":"2024062118401572000_2024.06.17.599454v1.9","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080845"},{"key":"2024062118401572000_2024.06.17.599454v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0741-5214(03)00148-4"},{"key":"2024062118401572000_2024.06.17.599454v1.11","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2001.111805"},{"key":"2024062118401572000_2024.06.17.599454v1.12","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313187"},{"key":"2024062118401572000_2024.06.17.599454v1.13","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.302175"},{"key":"2024062118401572000_2024.06.17.599454v1.14","doi-asserted-by":"crossref","unstructured":"Wickline SA , Hou KK and Pan H . Peptide-Based Nanoparticles for Systemic Extrahepatic Delivery of Therapeutic Nucleotides. Int J Mol Sci. 2023;24.","DOI":"10.3390\/ijms24119455"},{"key":"2024062118401572000_2024.06.17.599454v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.051627098"},{"key":"2024062118401572000_2024.06.17.599454v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.07.012"},{"key":"2024062118401572000_2024.06.17.599454v1.17","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309999"},{"key":"2024062118401572000_2024.06.17.599454v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAD347"},{"key":"2024062118401572000_2024.06.17.599454v1.19","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1383.029"},{"key":"2024062118401572000_2024.06.17.599454v1.20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203228"},{"key":"2024062118401572000_2024.06.17.599454v1.21","doi-asserted-by":"crossref","unstructured":"Yan H , Hu Y , Akk A , Rai MF , Pan H , Wickline SA and Pham CTN . Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis. Pharmaceutics. 2020;12.","DOI":"10.3390\/pharmaceutics12010073"},{"key":"2024062118401572000_2024.06.17.599454v1.22","doi-asserted-by":"crossref","first-page":"213009","DOI":"10.1016\/j.bioadv.2022.213009","article-title":"Peptide-siRNA nanoparticles targeting NF-kappaB p50 mitigate experimental abdominal aortic aneurysm progression and rupture","volume":"139","year":"2022","journal-title":"Biomater Adv"},{"key":"2024062118401572000_2024.06.17.599454v1.23","doi-asserted-by":"crossref","first-page":"935","DOI":"10.3892\/etm.2017.4048","article-title":"MicroRNA-17-5p mediates hypoxia-induced autophagy and inhibits apoptosis by targeting signal transducer and activator of transcription 3 in vascular smooth muscle cells","volume":"13","year":"2017","journal-title":"Exp Ther Med"},{"key":"2024062118401572000_2024.06.17.599454v1.24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40659-023-00418-5","article-title":"Enrichment of miR-17-5p enhances the protective effects of EPC-EXs on vascular and skeletal muscle injury in a diabetic hind limb ischemia model","volume":"56","year":"2023","journal-title":"Biol Res"},{"key":"2024062118401572000_2024.06.17.599454v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1599-9"},{"key":"2024062118401572000_2024.06.17.599454v1.26","doi-asserted-by":"crossref","first-page":"e23635","DOI":"10.1096\/fj.202400306R","article-title":"MicroRNA-181 in cardiovascular disease: Emerging biomarkers and therapeutic targets","volume":"38","year":"2024","journal-title":"FASEB J"},{"key":"2024062118401572000_2024.06.17.599454v1.27","doi-asserted-by":"crossref","unstructured":"Stastna M . Proteomics as a Tool for the Study of Mitochondrial Proteome, Its Dysfunctionality and Pathological Consequences in Cardiovascular Diseases. Int J Mol Sci. 2023;24.","DOI":"10.3390\/ijms24054692"},{"key":"2024062118401572000_2024.06.17.599454v1.28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s40139-019-00196-4","article-title":"Nanotherapies for Treatment of Cardiovascular Disease: A Case for Antioxidant Targeted Delivery","volume":"7","year":"2019","journal-title":"Curr Pathobiol Rep"},{"key":"2024062118401572000_2024.06.17.599454v1.29","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-153130"},{"key":"2024062118401572000_2024.06.17.599454v1.30","doi-asserted-by":"publisher","DOI":"10.1021\/nn403311c"},{"key":"2024062118401572000_2024.06.17.599454v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2013.01.037"},{"key":"2024062118401572000_2024.06.17.599454v1.32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI75673"},{"key":"2024062118401572000_2024.06.17.599454v1.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608245113"},{"key":"2024062118401572000_2024.06.17.599454v1.34","doi-asserted-by":"crossref","first-page":"e0203350","DOI":"10.1371\/journal.pone.0203350","article-title":"Associations and interactions between variants in selenoprotein genes, selenoprotein levels and the development of abdominal aortic aneurysm, peripheral arterial disease, and heart failure","volume":"13","year":"2018","journal-title":"PloS One"},{"key":"2024062118401572000_2024.06.17.599454v1.35","first-page":"9916881","article-title":"Construction of the circRNA-miRNA-mRNA Regulatory Network of an Abdominal Aortic Aneurysm to Explore Its Potential Pathogenesis","volume":"2021","year":"2021","journal-title":"Dis Markers"},{"key":"2024062118401572000_2024.06.17.599454v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.10.442"},{"key":"2024062118401572000_2024.06.17.599454v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2013.05.027"},{"key":"2024062118401572000_2024.06.17.599454v1.38","first-page":"6237960","article-title":"Mitochondrial Dysfunction and Increased DNA Damage in Vascular Smooth Muscle Cells of Abdominal Aortic Aneurysm (AAA-SMC)","volume":"2023","year":"2023","journal-title":"Oxid Med Cell Longev"},{"key":"2024062118401572000_2024.06.17.599454v1.39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/eurjpc\/zwad271","article-title":"Oxidative stress-related genetic variation and antioxidant vitamin intake in intact and ruptured abdominal aortic aneurysm: a Swedish population-based retrospective cohort study","volume":"31","year":"2024","journal-title":"Eur J Prev Cardiol"},{"key":"2024062118401572000_2024.06.17.599454v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2013.03.022"},{"key":"2024062118401572000_2024.06.17.599454v1.41","doi-asserted-by":"crossref","unstructured":"Annesley SJ and Fisher PR . Mitochondria in Health and Disease. Cells. 2019;8.","DOI":"10.3390\/cells8070680"},{"key":"2024062118401572000_2024.06.17.599454v1.42","doi-asserted-by":"crossref","unstructured":"Camacho-Encina M , Booth LK , Redgrave RE , Folaranmi O , Spyridopoulos I and Richardson GD. Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease. Cells. 2024;13.","DOI":"10.20944\/preprints202401.0975.v1"},{"key":"2024062118401572000_2024.06.17.599454v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/nature05292"},{"key":"2024062118401572000_2024.06.17.599454v1.44","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.9235"},{"key":"2024062118401572000_2024.06.17.599454v1.45","first-page":"II161","article-title":"Autopsy study of unoperated abdominal aortic aneurysms. The case for early resection","volume":"56","year":"1977","journal-title":"Circulation"},{"key":"2024062118401572000_2024.06.17.599454v1.46","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1148\/radiol.212323","article-title":"MR Elastography of Abdominal Aortic Aneurysms: Relationship to Aneurysm Events","volume":"304","year":"2022","journal-title":"Radiology"},{"key":"2024062118401572000_2024.06.17.599454v1.47","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3109\/09537100903137314","article-title":"The platelet protein kinase C substrate pleckstrin binds directly to SDPR protein","volume":"20","year":"2009","journal-title":"Platelets"},{"key":"2024062118401572000_2024.06.17.599454v1.48","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01325"},{"key":"2024062118401572000_2024.06.17.599454v1.49","doi-asserted-by":"crossref","first-page":"100106","DOI":"10.1016\/j.jvssci.2023.100106","article-title":"Thrombosis in the pathogenesis of abdominal aortic aneurysm","volume":"4","year":"2023","journal-title":"JVS Vasc Sci"},{"key":"2024062118401572000_2024.06.17.599454v1.50","doi-asserted-by":"crossref","first-page":"e1331722","DOI":"10.1080\/21688370.2017.1331722","article-title":"Roles of transient receptor potential channels in regulation of vascular and epithelial barriers","volume":"5","year":"2017","journal-title":"Tissue Barriers"},{"key":"2024062118401572000_2024.06.17.599454v1.51","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150353"},{"key":"2024062118401572000_2024.06.17.599454v1.52","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.it.2023.09.002","article-title":"Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion","volume":"44","year":"2023","journal-title":"Trends Immunol"},{"key":"2024062118401572000_2024.06.17.599454v1.53","doi-asserted-by":"crossref","first-page":"1240132","DOI":"10.3389\/fimmu.2023.1240132","article-title":"T cells in abdominal aortic aneurysm: immunomodulation and clinical application","volume":"14","year":"2023","journal-title":"Front Immunol"},{"key":"2024062118401572000_2024.06.17.599454v1.54","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5080843"},{"key":"2024062118401572000_2024.06.17.599454v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0305-6"},{"key":"2024062118401572000_2024.06.17.599454v1.56","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1038\/s41419-022-05462-9","article-title":"Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis","volume":"13","year":"2022","journal-title":"Cell Death Dis"},{"key":"2024062118401572000_2024.06.17.599454v1.57","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1038\/s41467-024-45823-w","article-title":"Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2024062118401572000_2024.06.17.599454v1.58","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1161\/CIRCULATIONAHA.123.066110","article-title":"Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis","volume":"149","year":"2024","journal-title":"Circulation"},{"key":"2024062118401572000_2024.06.17.599454v1.59","doi-asserted-by":"crossref","unstructured":"Morgan S , Lee LH , Halu A , Nicolau JS , Higashi H , Ha AH , Wen JR , Daugherty A , Libby P , Cameron SJ , et al. Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology. Front Cardiovasc Med. 2022;9:889994.","DOI":"10.3389\/fcvm.2022.889994"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.06.17.599454","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:35:13Z","timestamp":1768458913000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.06.17.599454"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,18]]},"references-count":59,"URL":"https:\/\/doi.org\/10.1101\/2024.06.17.599454","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.7150\/thno.104957","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,6,18]]},"subtype":"preprint"}}