Affiliation:
1. School of Pharmaceutical Sciences (Shenzhen) Shenzhen Campus of Sun Yat‐sen University Shenzhen 518107 China
2. Department of Pharmacy The Seventh Affiliated Hospital Sun Yat‐Sen University Shenzhen 518107 China
3. Department of Kidney Transplantation Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 China
Abstract
AbstractHeart 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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province
Shenzhen Science and Technology Innovation Program
National Key Research and Development Program of China