SDF-1α mRNA therapy in peripheral artery disease

Abstract

Stromal cell-derived factor-1 alpha (SDF-1α) is a promising target for therapeutic angiogenesis in ischemic diseases such as peripheral artery disease (PAD). However, the clinical application of SDF-1α protein or plasmid-based gene therapy is unsuccessful. mRNA therapy has shown great promise in protein replacement. Here, we developed DOPE-lipid nanoparticles (LNPs) encapsulating SDF-1α mRNA (LNP@SDF-1α) for efficient gene delivery. In vitro, LNP@SDF-1α treatment of human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial migration, tube formation, and increased monocyte adhesion, demonstrating robust pro-angiogenic activity. In vivo, LNP@SDF-1α transfected HUVECs showed enhanced angiogenic capacity in a murine Matrigel plug model. Furthermore, in a mouse hindlimb ischemia model, intramuscular injection of LNP@SDF-1α into ischemic limbs accelerated blood flow recovery, as assessed by laser speckle contrast imaging. Immunofluorescence staining revealed a marked increase in capillary and arteriole densities in treated tissues. Angiogenic protein profiling demonstrated an upregulation of pro-angiogenic factors, including VEGF and Ang-1, and a downregulation of anti-angiogenic factors. No significant toxicity was observed in major organs, indicating the safety of this approach. Our study demonstrates that SDF-1α mRNA therapy, delivered via DOPE-LNPs, significantly promotes vascular regeneration in ischemic tissues by enhancing angiogenesis and arteriogenesis, thereby restoring blood perfusion. This approach presents a promising therapeutic option for PAD and suggests broader applications of mRNA-based therapies for ischemic diseases.