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In this study, a niosomal formulation of vanillic acid was successfully developed to enhance its poor aqueous solubility and antioxidant therapeutic potential. Niosomes were prepared using Span 60 and cholesterol via thin-film hydration method followed by probe sonication and were optimized using a Box-Behnken design. The optimized formulation exhibited a vesicle size of 129.91 ± 2.78 nm, a polydispersity index (PDI) of 0.152 ± 0.06, a zeta potential of - 8.698 ± 0.52 mV, and an entrapment efficiency (EE%) of 35.893 ± 3.45%. Physicochemical analyses confirmed spherical morphology and amorphous drug dispersion. In vitro drug release showed a sustained profile governed by the Korsmeyer-Peppas model, indicating diffusion-controlled release as the main mechanism. Antioxidant assays, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), revealed significantly elevated enzymatic activity in the nanoformulation-treated groups. In vivo evaluation using a diabetic Wistar rat model showed that the 1% Niosome-Vanillic Acid containing formulation led to superior wound closure, increased hydroxyproline content, and improved histopathological features. These findings highlighted nano-encapsulated vanillic acid as a promising therapeutic strategy for diabetic wound healing.