Abstract

Skin pigmentation is primarily driven by ultraviolet A (UVA)-induced oxidative stress and melanogenesis. Glabridin (Gla), known for its potent antimelanogenesis activity, encounters application challenges owing to its limited transdermal absorption. Here, based on the antimelanogenesis and antioxidant activities of German chamomile as well as the advantages of extracellular vesicles produced by living cells in overcoming the skin barrier and ensuring biological safety, we developed a transdermal drug delivery system that uses German chamomile-derived extracellular vesicles (GCEVs) to encapsulate Gla (GCEVs@Gla). This system aims to promote the transdermal absorption of Gla and enhance its antimelanogenesis efficacy, leveraging the inherent biological properties of GCEVs. Physicochemical characterization confirmed that GCEVs@Gla maintained favorable nanosize and morphological properties. Compared with free Gla, GCEVs@Gla exhibited optimized skin penetration and retention. In vitro and in vivo evaluations demonstrated that GCEVs@Gla modulated key genes (NFE2L2, HMGB1, POMC, MC1R, MITF, and TYR) and significantly suppressed UVA-induced oxidative stress and melanogenesis, ultimately effectively inhibiting pigmentation. Furthermore, the biotoxicity of Gla was mitigated after being encapsulated by the GCEVs. Notably, bioinformatics analysis revealed that GCEVs regulated pigmentation through multitarget modulation of the oxidative stress-inflammatory cascade and melanin synthesis, highlighting the potential of GCEVs as natural carriers in dermatological applications. The GCEVs@Gla strategy, combining efficient transdermal delivery and bioactive synergy, offers a promising approach for controlling UVA-induced pigmentation and skin photodamage.