Dual-mechanism vitamin C delivery by polyethylene glycol-23 glyceryl distearate-based niosomes via SVCT2 induction and enhanced transdermal penetration.

Polyethylene glycol-23 glyceryl distearate (GDS-23)-a noisome-forming diacylglycerol-polyethylene glycol-based nonionic surfactant-functions as a nanocarrier for drug delivery systems (DDS) and an enhancer of endogenous antioxidant capacity through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Here, we evaluated the potential of GDS-23 as a multifunctional DDS carrier by investigating the combined contribution of (i) improved transdermal delivery mediated by niosomal DDS and (ii) increased cellular uptake associated with induction of antioxidant-related transporters, using protection against oxidative-stress-induced tissue damage as a functional readout. We determined whether GDS-23 modulates the expression of the antioxidant-related transporters xCT and SVCTs through Nrf2 activation. In normal human epidermal keratinocytes, GDS-23 treatment significantly upregulated the mRNA expression of xCT (SLC7A11; cystine/glutamate antiporter) and sodium-dependent vitamin C transporter 2 (SVCT2). The induction was diminished by an Nrf2 activation inhibitor (K67), indicating involvement of the Nrf2 pathway. Furthermore, evaluation using a three-dimensional reconstructed epidermis model with calcein sodium as a fluorescent tracer revealed that GDS-23-based niosomes facilitated skin permeation. When L-ascorbic acid or cysteine was encapsulated within these niosomes, hydroquinone-induced oxidative tissue damage was attenuated, with the L-ascorbic acid-loaded niosomes exhibiting the most prominent protective effect. Overall, this study shows that Nrf2 activation contributes to SVCT2 induction and that GDS-23 is a multifunctional DDS nanocarrier that enhances skin permeation and may promote intracellular uptake by upregulating antioxidant-related transporters. These findings highlight the therapeutic potential of combining functional nanocarriers with entrapped bioactive molecules, offering a promising strategy for efficient treatment of skin disorders and antioxidant-based interventions.