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Here, we report a multivalent bi\u2010specific nanoerythrosome for thrombus\u2010targeted delivery of tissue plasminogen activator (tPA) (denoted as mBiNE@tPA) to achieve effective thrombolysis. This bio\u2010inspired delivery system was fabricated to exploit two main thrombus components by utilizing the natural erythrocyte membrane for homologous targeting to a thrombus and fibrinogen\u2010derived cyclic arginine\u2010glycine\u2010aspartic acid (cRGD) motifs for active targeting to activated platelets. mBiNE@tPA maintained tPA's activity during extended circulation. Its preferential thrombus accumulation, enhanced thrombus penetration, and triggered tPA release locally through the combined homologous and active thrombus targeting were demonstrated. Efficient and selective fibrinolysis and thrombolysis both in vitro and in vivo were achieved, leading to effective vascular recanalization with minimal hemorrhagic risks in mice. Through the combined experimental and computational work, mBiNE@tPA exhibited superior thrombolytic capabilities over formulations with single or no targeting specificity and free tPA. This nanoerythrosome represents a promising platform for targeted therapies.<\/jats:p>","DOI":"10.1002\/smll.74578","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:23:14Z","timestamp":1783934594000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multivalent Bi\u2010Specific Nanoerythrosomes: A Two\u2010Birds\u2010One\u2010Stone Approach to Combine Homologous and Active Targeting for Effective Thrombolysis"],"prefix":"10.1002","volume":"22","author":[{"given":"Yu","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Imperial College London South Kensington Campus  London UK"},{"name":"Department of Radiology Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Sixth People's Hospital  Shanghai P. R. 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