Lipid Nanoparticles Enable Efficient EGF mRNA Delivery for Wound Healing

<b>Background:</b> The process of healing skin wounds frequently faces obstacles due to inadequate repair. Even though recombinant Epidermal Growth Factor (EGF) is a significant therapeutic agent, its short half-life and instability limit its clinical application. The study's objective was to establish a lipid nanoparticle (LNP) delivery method for efficiently transporting EGF mRNA, with the goal of achieving sustained local protein expression to aid in wound healing. <b>Methods:</b> EGF mRNA was produced through in vitro transcription and enclosed in pH-sensitive LNPs using microfluidic techniques. The LNP-mRNAEGF's physicochemical attributes, stability, and biocompatibility were assessed. Its effects on the proliferation and migration of HaCaT cells and on EGF expression were assessed in vitro. The therapeutic effectiveness was assessed using a mouse model with full-thickness skin defects and compared to control groups (saline, empty LNP, recombinant EGF). The study analyzed wound closure rate, histology, immunofluorescence, and systemic safety. <b>Results:</b> The LNP-mRNA_EGF formulation showed a spherical shape and demonstrated good stability. In vitro, it showed excellent biocompatibility, facilitated prolonged EGF expression in HaCaT cells depending on the dose for more than 72 h, and greatly enhanced cell proliferation and migration. In vivo, a single dose of LNP-mRNA_EGF greatly sped up wound healing, almost completely closing the wound by day 10, and was much more effective than all control groups. Histological and immunofluorescence analyses revealed enhanced re-epithelialization, significantly increased and optimized collagen I/III deposition, and an upregulated expression of EGF and E-cadherin. Moreover, no significant toxicity was found in the systemic safety assessment. <b>Conclusions:</b> The LNP-based EGF mRNA delivery platform enables efficient and sustained local protein expression via a single administration. It offers a promising translational strategy for protein replacement therapy in skin repair by significantly accelerating wound healing through enhanced re-epithelialization and optimized collagen remodeling.