Inflammation-directed nanozyme-eluting hydrogel coating promotes vascular tissue repair by restoring reactive oxygen species homeostasis

Thrombosis and stenosis remain two of the most prevalent complications of vascular implants. The most effective strategy in clinics to inhibit stenosis is based on the eluting of anti-hyperplasia drugs such as sirolimus and everolimus while it also has been known to hinder vascular healing and regeneration. Selectively inhibiting intimal hyperplasia and promoting endothelialization remains a highly challenging target for vascular implants. Due to auto-regenerative antioxidant activity nanoceria as a nanozyme has been widely used to regulate oxidative stress in the treatment of inflammation-related diseases. Yet the application of nanozyme in vascular implants has not hitherto been reported. In this study we constructed a reactive oxygen species (ROS)-targeted nanoceria-eluting degradable zwitterion hydrogel coating on membrane-covered stents with favorable anti-coagulation pro-endothelialization and immunomodulation properties. The hydrogel coating exhibited excellent hemocompatibility and simultaneously promoted the growth of endothelial cells. Nanoceria embedded in hydrogel could be released in response to matrix metalloproteinase (MMP) and effectively scavenge artificial and intracellular ROS via mimicking the activity of natural superoxide dismutase (SOD) and catalase (CAT). In addition the incorporation of nanoceria increased the expression levels of anti-inflammation cytokines and growth factors and reduced the expression levels of pro-inflammation cytokines in macrophages inducing a switch of macrophage phenotype from M1 to M2. The membrane-covered stent based on nanozyme-integrated hydrogel-coated PLLA membrane exhibited a high patency rate and slight intima hyperplasia degree upon implantation into rabbits' iliac arteries/abdominal aortas. This advanced hydrogel coating may provide a new low-cost and drug-free strategy for effectively inhibiting vascular stenosis and promoting vascular repair.