Liposome-iRGD loaded with astragaloside IV alleviates the functional damage of endothelial progenitor cells via the Hippo-YAP/TAZ signaling pathway.

The characteristics of diabetic vascular complications are impaired angiogenesis, which leads to hindlimb ischemia. Although astragaloside IV (AS-IV) can promote angiogenesis, its poor targeting to endothelial progenitor cells (EPCs) limits its therapeutic effect. Here, we developed liposomes modified with iRGD to load AS-IV (Lp-iRGD@AS-IV) to enhance its delivery and explored its mechanism. Lp-iRGD@AS-IV and fluorescently labeled liposomes were prepared, and their phenotypic characteristics were detected. The study results showed that the uptake efficiency of Lp-iRGD@AS-IV by EPCs was higher than that of Lp@AS-IV. In a diabetic mouse hindlimb ischemia model induced by streptozotocin, Lp@AS-IV and Lp-iRGD@AS-IV improved cell damage, increased capillary density, and reduced reactive oxygen species accumulation. However, the therapeutic effect of Lp-iRGD@AS-IV was more significant than that of Lp@AS-IV. Lp-iRGD@AS-IV attenuated high glucose-induced inhibitory effect on cell viability, migration, and invasion capability of EPCs. Additionally, we analyzed the regulatory effects of the Hippo-YAP/TAZ signaling pathway in diabetic vascular complications. AS-IV increased the expression of vascular growth factors (VEGFa, VEGFb, VEGFc, FGF, and Ang-1), eNOS, and osteopontin, and enhanced glucose-lipid metabolism, via activating the upstream Hippo signaling pathway while inactivating the downstream YAP/TAZ activity. In conclusion, Lp-iRGD@AS-IV significantly enhanced the delivery of AS-IV to EPCs and improved hindlimb ischemia in diabetic mice. AS-IV can restore diabetes-associated impaired angiogenesis through the Hippo-YAP/TAZ pathway. Lp-iRGD@AS-IV may be a targeted therapy for diabetic vascular complications.