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Lipid\u2010based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase\u2010type plasminogen activator (uPA) and coated with a low\u2010fouling peptide that is incorporated within a metal\u2013phenolic network (MPN). The peptide\u2010containing MPN (pep\u2010MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep\u2010MPN\u2010coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane\u2010dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA\u2010loaded pep\u2010MPN\u2010coated cubosomes demonstrate significantly reduced nonspecific cell association (&lt;10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half\u2010life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane\u2010dependent release of uPA within pep\u2010MPN\u2010coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.<\/jats:p>","DOI":"10.1002\/adhm.202201151","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T18:48:56Z","timestamp":1661798936000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Polyphenol\u2010Functionalized Cubosomes as Thrombolytic Drug Carriers"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7700-2392","authenticated-orcid":false,"given":"Haitao","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering The University of Melbourne  Parkville Victoria 3010 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