ML228-loaded nanoparticles with platelet membrane coating promote endothelialization of vascular grafts by enhancing HIF-1α expression

Small-diameter vascular grafts (SDVGs) often struggle to maintain long-term patency due to thrombus formation, intimal hyperplasia, and inflammation. Endothelialization emerges as a pivotal strategy for addressing these concerns. As a representative activator of the hypoxia-inducible factor (HIF) pathway, ML228 can stimulate the expression of downstream target genes like vascular endothelial growth factor (VEGF) to induce angiogenesis, yet it requires encapsulation by nanoparticles for optimal delivery and efficacy. However, the immune system often recognizes nanoparticles as foreign entities, posing a significant risk of clearance. In this study, we developed ML228-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles and coated them with platelet membranes, thereby enhancing their biocompatibility and enabling immune escape. The ML228-loaded PLGA nanoparticles coated with platelet membranes (MPNP) were immobilized onto electrospinning SDVGs made of silk fibroin (SF) and polycaprolactone (PCL) to obtain MPNP-coated grafts (SF/PCL@MPNP) with the ability to promote endothelialization. In vitro biological activity studies demonstrated that SF/PCL@MPNP activated the HIF pathway, upregulating the downstream target gene VEGF, which facilitated endothelial cells migration and angiogenesis. In vivo implantation in a rat abdominal aorta model revealed that SF/PCL@MPNP promoted endothelialization, supported the regeneration of contractile smooth muscle cells, and modulated inflammatory responses. Overall, this study presents a strategy for constructing SDVGs using ML228-loaded nanoparticles with platelet membrane coating, highlighting the promises of using ML228 to activate the HIF pathway and membrane-coated nanoparticles to improve endothelialization in vascular graft applications.