Thrombin-responsive curcumin liposome-modified vascular grafts for improved antithrombosis and vascular regeneration

A thrombin-responsive curcumin liposome-modified PCL/PLGA vascular graft (uPA-Cur-PDA@PCL/PLGA) was developed. • uPA-Cur-PDA@PCL/PLGA enabled on-demand uPA release for thrombolysis upon thrombin stimulation. • uPA-Cur-PDA@PCL/PLGA scavenged ROS and promoted M2 macrophage polarization via curcumin liposomes. • In vivo, uPA-Cur-PDA@PCL/PLGA maintained 3-month patency, promoted endothelialization, and reduced inflammation. • This strategy offers a promising approach for antithrombosis and vascular regeneration in small-diameter vascular grafts. The failure of small-diameter vascular grafts (SDVGs) is primarily attributed to thrombosis and pathological inflammation, leading to incomplete endothelialization and ultimately poor long-term patency. Current antithrombotic strategies are limited by insufficient durability and the risk of systemic coagulation disturbances associated with continuous anticoagulation. Herein, we developed a thrombin-responsive vascular graft enabling on-demand thrombolysis and modulation of the pathological microenvironment. Curcumin was encapsulated into liposomes to overcome its poor bioavailability, endowing the graft with reactive oxygen species (ROS) scavenging and immunomodulatory effects. Thrombin-responsive curcumin-loaded liposomes (uPA-Cur-Lip) were then constructed by sequentially conjugating a thrombin-cleavable peptide and urokinase-type plasminogen activator (uPA) to the liposomes. Subsequently, uPA-Cur-Lip was immobilized onto electrospun PCL/PLGA vascular grafts via polydopamine (PDA) coating, yielding uPA-Cur-PDA@PCL/PLGA. In vitro studies confirmed sustained curcumin release from the liposomes and thrombin-responsive "on-demand" thrombolytic activity. Furthermore, uPA-Cur-PDA@PCL/PLGA enhanced endothelial cell migration, alleviated oxidative stress, and promoted M2 macrophage polarization. The results of in vivo rat abdominal aorta implantation showed that uPA-Cur-PDA@PCL/PLGA exhibited sustained patency for 3 months without thrombosis, along with improved endothelialization and reduced inflammation. Overall, we developed a thrombin-responsive curcumin liposome-modified SDVG that enables on-demand thrombolysis and modulates the local microenvironment, thereby promoting vascular regeneration and improving long-term graft performance. Download: Download high-res image (194KB) Download: Download full-size image