{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:44:14Z","timestamp":1793083454178,"version":"4.5.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Thrombosis is a major contributor to morbidity and mortality in cardiovascular diseases. Although current antiplatelet therapies reduce thrombotic complications, they are associated with systemic bleeding complications. We previously developed a single-chain variable fragment (scFv) that specifically binds and blocks the activated platelet integrin \u03b1IIb\u03b23 (GPIIb\/IIIa [glycoprotein IIb\/IIIa]), preventing thrombosis without impairing hemostasis. We hypothesized that an mRNA-based therapeutic encoding scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      would offer prolonged expression and enhanced therapeutic durability while maintaining a favorable safety profile.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We designed and synthesized both conventional mRNA and self-amplifying mRNA constructs encoding scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      . The constructs were first validated in vitro by confirming their expression of a functional scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      . For in vivo experiments, mRNAs were encapsulated in a novel lipid nanoparticle formulation comprising of \u03b3-oryzanol and DLin-KC2-DMA (OryKL) for systemic delivery. Their biosafety was assessed by a series of biochemical and histological examinations. The murine FeCl\n                      <jats:sub>3<\/jats:sub>\n                      -induced arterial thrombosis model was used to assess the preventive effect of scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      -encoding mRNAs on thrombus formation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      In vitro assays confirmed the efficient expression and secretion of a functional scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      that selectively bound to and blocked activated GPIIb\/IIIa, thereby inhibited platelet aggregation. In mice with induced thrombosis, OryKL-delivered scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      mRNA significantly prolonged occlusion time at 24 hours posttreatment, while self-amplifying mRNA provided sustained thromboprotection for over 7 days. Tail bleeding times were unchanged across all groups, and no systemic toxicity or histopathologic abnormalities were observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that scFv\n                      <jats:sub>\u03b1IIb\u03b23<\/jats:sub>\n                      mRNA and self-amplifying mRNA therapeutics enable safe, effective, and long-acting antithrombotic protection in vivo, offering a promising strategy for thromboprophylaxis that prevents the bleeding risks associated with current antiplatelet therapies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327626","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T13:37:56Z","timestamp":1779111476000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Platelet-Targeted Self-Amplifying mRNA for Safe, Long-Acting Thromboprophylaxis"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0973-2078","authenticated-orcid":true,"given":"Yuyang","family":"Song","sequence":"first","affiliation":[{"name":"Molecular Imaging and Nanotherapeutics Laboratory (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Centre for Cardiometabolic mRNA Therapy (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., K.P., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Department of Cardiometabolic Health, Melbourne Medical School, University of Melbourne, Victoria, Australia (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., J.I.S., H.L., M.L.P.V., K.P., X.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8378-555X","authenticated-orcid":true,"given":"Thanh Hung","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Nanotherapeutics Laboratory (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Centre for Cardiometabolic mRNA Therapy (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., K.P., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Department of Cardiometabolic Health, Melbourne Medical School, University of Melbourne, Victoria, Australia (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., J.I.S., H.L., M.L.P.V., K.P., X.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengkai","family":"Shi","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Nanotherapeutics Laboratory (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Centre for Cardiometabolic mRNA Therapy (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., A.N., H.L., M.L.P.V., K.P., X.W.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia."},{"name":"Department of Cardiometabolic Health, Melbourne Medical School, University of Melbourne, Victoria, Australia (Y.S., T.H.N., P.S., A.R., C.V.P., B.X., S.R., J.I.S., H.L., M.L.P.V., K.P., X.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0353-4935","authenticated-orcid":true,"given":"Ahmed","family":"Refaat","sequence":"additional","affiliation":[{"name":"Molecular Imaging and Nanotherapeutics 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