Reactive Oxygen Species Responsive Multifunctional Fusion Extracellular Nanovesicles: Prospective Treatments for Acute Heart Transplant Rejection

Abstract Heart transplantation offers life‐saving treatment for patients with end‐stage heart failure; however, ischemia‐reperfusion injury (IRI) and subsequent immune responses remain significant challenges. Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant‐derived vesicle‐like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)‐responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6C⁺Ly6G⁻ inflammatory macrophage‐mediated rejection in heart transplantation. The FNVs comprise Exocarpium Citri grandis‐derived extracellular nanovesicles with anti‐inflammatory and antioxidant properties, and mesenchymal stem cell membrane‐derived nanovesicles expressing calreticulin with macrophage‐targeting ability. A novel ROS‐responsive bio‐orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6C⁺Ly6G⁻ inflammatory macrophages toward an anti‐inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion‐targeted delivery strategy offers superior heart graft site enrichment and macrophage‐specific targeting, promising improved transplant outcomes.