VCAM-1-targeting peptide assemblies protect vascular endothelium and prolong cardiac xenograft survival

Cardiac xenotransplantation represents a promising strategy to address the shortage of donor hearts, yet endothelial cell dysfunction remains a major obstacle to long-term graft survival. Using integrated single-cell RNA sequencing in a porcine-to-primate xenotransplantation model, we identified a VCAM-1⁺ endothelial subpopulation as the primary endothelial subtype susceptible to acute rejection, characterized by its selective depletion after transplantation. To protect this population, we develop VCAM-1-targeted nanoparticles (VTNs) integrating three functional modules: (i) a VCAM-1-binding peptide identified, (ii) a self-assembling peptide module by one-bead one-compound screening for precise targeting that forms protective nanofibrous coatings, and (iii) localized delivery of mycophenolate mofetil (MMF) for immune modulation. VTN reduces immune cell adhesion by 73% (P < 0.001) and extends xenograft survival nearly fourfold, from 6.7 to 27.0 days. These findings establish VCAM-1⁺ endothelial cells as a therapeutic target and highlight VCAM-1-targeted nanomedicine as a promising approach to improve xenograft outcomes.