Ferulic acid liposomes improve diabetic EPC angiogenesis by upregulating the AMPK/KLF4/FAM3A pathway

Diabetic vascular complications are a leading cause of disability in diabetic. This study aimed to investigate the functional improvement effects and molecular mechanisms of internalizing RGD (iRGD) peptide-modified ferulic acid-targeted liposomes (Lp-iRGD@FA) on high glucose-induced injured endothelial progenitor cells (EPCs). Lp-iRGD@FA was prepared using the thin-film hydration method and subsequently characterized. In vitro experiments were conducted using human peripheral blood-derived EPCs, in which a high glucose injury model was established. Cells were treated with free ferulic acid, non-targeted liposomes, and targeted liposomes, respectively. In vivo, a diabetic hindlimb ischemia mouse model was established, and Lp-iRGD@FA, non-targeted liposomes, or Lp-iRGD were intramuscularly injected into the ischemic muscles. The high glucose environment significantly inhibited EPC proliferation, promoted apoptosis, and impaired tube formation ability, accompanied by inhibited AMPK phosphorylation and downregulated expression of KLF4 and FAM3A. Intervention with the targeted liposomes effectively reversed these changes. However, the AMPK inhibitor Compound C blocked the Lp-iRGD@FA-induced upregulation of KLF4 and FAM3A and the associated functional improvements, whereas KLF4 supplementation partially rescued the decreased FAM3A expression and impaired tube formation caused by AMPK inhibition. In vivo, Lp-iRGD@FA treatment in diabetic mice enhanced angiogenesis in a hindlimb ischemia model and activated the AMPK/KLF4/FAM3A pathway in ischemic muscles. This study demonstrates that Lp-iRGD@FA efficiently delivers ferulic acid to restore FAM3A expression by activating the AMPK/KLF4/FAM3A signaling axis, subsequently upregulating VEGFA/VEGFR2 levels and improving the function of EPCs under high glucose stress. These findings provide a novel nanomedicine strategy and potential molecular targets for the treatment of diabetic vascular complications.