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However, the clinical application of SDF-1\u03b1 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-1\u03b1 mRNA (LNP@SDF-1\u03b1) for efficient gene delivery. In vitro, LNP@SDF-1\u03b1 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-1\u03b1 transfected HUVECs showed enhanced angiogenic capacity in a murine Matrigel plug model. Furthermore, in a mouse hindlimb ischemia model, intramuscular injection of LNP@SDF-1\u03b1 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-1\u03b1 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.<\/jats:p>","DOI":"10.1007\/s10456-025-09979-3","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:23:32Z","timestamp":1746174212000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["SDF-1\u03b1 mRNA therapy in peripheral artery disease"],"prefix":"10.1007","volume":"28","author":[{"given":"Tinghong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binqiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"9979_CR1","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1016\/S0140-6736(13)61249-0","volume":"382","author":"FG Fowkes","year":"2013","unstructured":"Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH (2013) Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. 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