Topical VEGF-A mRNA therapy promotes angiogenesis and accelerates wound healing

Promoting angiogenesis through supplementation of pro-angiogenic cytokines accelerates wound healing, yet clinical application has been hindered by high costs, short half-life, and adverse effects. Messenger RNA (mRNA) therapy offers a safer, more scalable alternative, but whether topical mRNA delivery can withstand RNase-rich wound environments and exert therapeutic benefits remains unclear. Here, we developed an optimized ionizable lipid nanoparticle (LNP) formulation incorporating DOPE for the delivery of Vascular endothelial growth factor-A 165 (VEGF-A 165 ) mRNA (LNP@VEGF) and evaluated its capacity to enhance angiogenesis and wound healing. We demonstrated that LNP@VEGF effectively protected mRNA from degradation and enabled robust VEGF-A expression in vitro , promoting endothelial proliferation and tube formation. Importantly, topical application of LNP@VEGF in a murine excisional wound model led to sustained VEGF-A mRNA expression, enhanced angiogenesis, and accelerated wound closure. Together, these findings establish topical LNP-delivered mRNA therapy as a non-invasive and effective strategy for regenerative angiogenesis, thereby opening new avenues for treating non-healing skin wounds. • DOPE-containing LNPs enable topical mRNA delivery in RNase-rich wound environments. • VEGF-A mRNA-LNPs promote endothelial proliferation and tube formation in vitro . • Topical application of VEGF-A mRNA-LNPs enhances angiogenesis and accelerates wound healing in vivo . • This study establishes a non-invasive mRNA therapy platform for cutaneous wound healing.