Diabetic foot ulcer (DFU) is one of the most serious and dreaded complications of diabetes and lack effective treatment options. Fibroblast Growth Factor 2 (FGF2) has been reported to play an important role in wound healing. However, it is difficult to sustainably deliver FGF2 to the wound site of DFU owing to its poor stability and easy degradation. In this study, we developed a lipid nanoparticle (LNP)-encapsulated circular RNA (circRNA) system encoding FGF2 to achieve sustained protein expression and promote diabetic wound healing. Unlike conventional FGF2 protein therapy and linear mRNA-based delivery, the LNP-circFGF2 system demonstrated prolonged FGF2 expression over an extended period following a single administration, due to the inherent stability of circRNA against exonuclease degradation. In vitro, LNP-circFGF2 significantly enhanced fibroblast proliferation and migration, as well as endothelial cell tube formation, compared to both FGF2 protein and linear mRNA treatments. In a diabetic mouse model of wound healing, LNP-circFGF2 accelerated wound closure and improved collagen deposition relative to control treatments. Histological and single cell RNAseq analyses confirmed superior re-epithelialization, angiogenesis, and extracellular matrix remodeling without significant immune response activation in the wound of LNP-circFGF2 treatment. This study establishes LNP-circFGF2 as a promising "single-dose, long-acting" therapeutic platform for DFU treatment, addressing key limitations of current cytokine therapies. By leveraging the stability of circRNA and efficient LNP delivery, this approach not only enhances diabetic wound healing but also offers a versatile framework for protein delivery in regenerative medicine.
