Oligoglycine and fluoropolymer functionalized enzyme-responsive gene delivery surface for rapid in situ endothelialization of vascular grafts

Abstract

The treatment success of small-caliber artificial vascular grafts is seriously limited by high thrombogenesis and low endothelialization. Gene transfection can effectively enhance the proliferation and migration of endothelial cells (ECs) and accelerating the formation of endothelium layer. How to efficiently and temporarily immobilize the gene complexes on the material surface, how to intelligently release them and effectively transfect ECs are still the challenges for in situ endothelialization. Herein, a matrix-metalloproteinase (MMP)-responsive gene delivery system is constructed for in situ smart release of genes from the graft surface. The fluorinated cationic polymer (F-ssPEI) is served as high-efficient and low-cytotoxic gene vector. The gene complexes are temporarily immobilized via a MMP-cleavable peptide (MCP) linker which contains a MMP-susceptible sequence as the principal part and oligoglycine sequence (Gm) with different units (m = 0, 4 and 8) as the flexible spacer arm. These gene delivery surfaces achieve the temporary immobilization, smart release and high internalization of gene complexes. The MCP(G8) group shows the highest transfection efficacy and the optimal HUVEC proliferation/migration/function. The enhanced endothelialization and contractile smooth muscle cell regeneration of grafts are achieved in vivo. The MMP-responsive gene delivery system provides an effective platform to promote regeneration of vascular graft.