Abstract：
Gene delivery presents great potential in endothelium regeneration and prevention of vascular diseases, but its outcome is inevitably limited by high shear stress and instable microenvironment. Highly efficient nanosystems may alleviate the problem with strong dual-specificity for diseased site and targeted cells. Hence, biomimetic coatings incorporating EC-targeting peptides were constructed by platelets and endothelial cells (ECs) for surface modification. A series of biomimetic gene complexes were fabricated by the biomimetic coatings to deliver pcDNA3.1-VEGF165 plasmid (pVEGF) for rapid recovery of endothelium. The gene complexes possessed good biocompatibility with macrophages, stability with serum and showed no evident cytotoxicity for ECs even at very high concentrations. Furthermore, the peptide modified gene complexes achieved selective internalization in ECs and significant accumulation in endothelium-injured site, especially the REDV-modified and EC-derived gene complexes. They substantially enhanced VEGF expression at mRNA and protein levels, thereby enabling a wound to heal completely within 24 h according to wound healing assay. In an artery endothelium-injured mouse model, the REDV-modified and EC-derived gene complexes presented efficient re-endothelialization with the help of enhanced specificity. The biomimetic gene complexes offer an efficient dual-targeting strategy for rapid recovery of endothelium, and hold potential in vascular tissue regeneration.
摘要：
基因传递在内皮再生和预防血管疾病方面具有巨大的潜力，但其结果不可避免地受到高剪切应力和不稳定的微环境的限制。高效纳米系统可以缓解对患病部位和靶细胞具有强双重特异性的问题。因此，通过血小板和内皮细胞（EC）构建掺入EC靶向肽的仿生涂层，以进行表面修饰。通过仿生涂层制备了一系列仿生基因复合物，以递送pcDNA3.1-VEGF165质粒（pVEGF），以快速恢复内皮。该基因复合物与巨噬细胞具有良好的生物相容性,即使在非常高的浓度下，对ECs也没有明显的细胞毒性。此外，肽修饰的基因复合物在内皮细胞中实现了选择性内化，并在内皮损伤部位实现了显著的积累，特别是REDV修饰的和EC衍生的基因复合物。它们在mRNA和蛋白质水平上显著增强了VEGF的表达，从而根据伤口愈合测定使伤口在24小时内完全愈合。在动脉内皮损伤的小鼠模型中,REDV修饰的和EC衍生的基因复合物在特异性增强的帮助下呈现有效的再内皮化。仿生基因复合物为内皮的快速恢复提供了有效的双靶向策略，并保持血管组织再生的潜力。
