Green tea–derived exosome-like nanoparticles attenuate oxidative stress–induced skin senescence via modulation of p38 MAPK signaling

Introduction Plant-derived exosome-like nanoparticles (PDENs) have emerged as bioactive nanostructures capable of transferring molecular cargos across species; however, their mechanistic roles in mammalian stress-responsive signaling remain incompletely defined. In this study, we investigated the effects of green tea ( Camellia sinensis (L.) Kuntze [Theaceae])–derived exosome-like nanoparticles (GtDENs) on oxidative stress–induced cellular dysfunction in human keratinocytes. Methods To do this, we employed MTT assay, immunoblotting analysis, real-time PCR method, SA-beta-gal assay, flowcytometry, and molecular docking model. Results and Discussion GtDENs exhibited no detectable cytotoxicity and significantly attenuated hydrogen peroxide– and UVB-induced reactive oxygen species (ROS) accumulation and cell death. GtDENs suppressed oxidative stress–associated cellular senescence and apoptotic gene expression, including MMP3, p21, and caspases. Mechanistically, GtDENs preferentially reduced phosphorylation of p38 MAPK and downstream c-Fos activation under oxidative stress conditions, while ERK and JNK signaling remained largely unaffected. Functional analyses, including p38 overexpression and pharmacological inhibition experiments, support the involvement of p38 MAPK signaling in mediating GtDEN activity. Phytochemical profiling identified caffeine as the predominant small-molecule component within GtDENs. Molecular docking and cellular thermal shift assays suggest potential interaction between caffeine and p38 MAPK, although direct biochemical binding validation was not performed. Exploratory small RNA profiling further indicated the presence of regulatory RNA species associated with stress-responsive pathways. Collectively, these findings indicate that GtDENs modulate oxidative stress–responsive signaling, with p38 MAPK emerging as a key signaling axis involved in this response.