VCAM-1-Targeting Peptide Assemblies Protect Endothelium, Quadrupling Cardiac Xenograft Survival

Cardiac xenotransplantation offers a solution to donor heart shortages, but endothelial cell dysfunction remains a critical barrier to long-term graft survival. Current strategies often fail to adequately protect the graft endothelium from acute rejection. This study addresses this gap by identifying a specific VCAM-1+ endothelial subpopulation as highly susceptible to rejection, paving the way for targeted therapeutic interventions to improve xenograft outcomes and overcome the limitations of broad immunosuppression.

Researchers used integrated single-cell RNA sequencing in a porcine-to-primate xenotransplantation model to identify endothelial cell subtypes. They then developed VCAM-1-targeted nanoparticles (VTNs), which incorporated three modules: (i) a novel VCAM-1-binding peptide, (ii) a self-assembling peptide for nanofibrous coating, and (iii) localized delivery of mycophenolate mofetil (MMF) for immune modulation. The VTNs were evaluated for their ability to reduce immune cell adhesion and prolong xenograft survival.

Integrated single-cell RNA sequencing revealed a distinct VCAM-1+ endothelial subpopulation as the primary endothelial subtype vulnerable to acute rejection, showing selective depletion post-transplantation.

VCAM-1-targeted nanoparticles (VTNs) significantly reduced immune cell adhesion by 73% (P < 0.001) in xenograft models. Crucially, VTN treatment extended cardiac xenograft survival nearly fourfold, increasing the median survival time from 6.7 days to 27.0 days. These findings underscore the critical role of VCAM-1+ endothelial cells as a therapeutic target and demonstrate the efficacy of this targeted nanomedicine approach in improving xenograft outcomes.