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Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant\u2010derived vesicle\u2010like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)\u2010responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6C\n                    <jats:sup>+<\/jats:sup>\n                    Ly6G\n                    <jats:sup>\u2212<\/jats:sup>\n                    inflammatory macrophage\u2010mediated rejection in heart transplantation. The FNVs comprise\n                    <jats:italic>Exocarpium Citri grandis<\/jats:italic>\n                    \u2010derived extracellular nanovesicles with anti\u2010inflammatory and antioxidant properties, and mesenchymal stem cell membrane\u2010derived nanovesicles expressing calreticulin with macrophage\u2010targeting ability. A novel ROS\u2010responsive bio\u2010orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6C\n                    <jats:sup>+<\/jats:sup>\n                    Ly6G\n                    <jats:sup>\u2212<\/jats:sup>\n                    inflammatory macrophages toward an anti\u2010inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion\u2010targeted delivery strategy offers superior heart graft site enrichment and macrophage\u2010specific targeting, promising improved transplant outcomes.\n                  <\/jats:p>","DOI":"10.1002\/adma.202406758","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T05:19:51Z","timestamp":1719033591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Reactive Oxygen Species Responsive Multifunctional Fusion Extracellular Nanovesicles: Prospective Treatments for Acute Heart Transplant Rejection"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8680-0361","authenticated-orcid":false,"given":"Xingyu","family":"Lu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen) Shenzhen Campus of Sun Yat\u2010sen University  Shenzhen 518107 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