<p>Nano- and microplastics (N/MPs) are emerging environmental contaminants increasingly detected in multiple human tissues, yet their biological effects remain poorly defined. The vaginal epithelium represents a relevant but largely unexplored site of exposure. Here, we investigated the metabolic and elemental responses of human vaginal keratinocytes (VK2 E6/E7) exposed to polyethylene (PE) N/MPs using an integrated transcriptomic and synchrotron imaging approach. Cells were challenged with environmentally relevant unlabeled PE N/MPs (200 nm - 9 µm) and with traceable PE quantum dot-labeled nanoparticles (PE QDs/NPs). NanoString nCounter analysis revealed widespread transcriptional alterations across metabolic processes, with activation of pro-inflammatory and oxidative stress pathways, dysregulation of lipid metabolism, and impaired cholesterol biosynthesis. Immune-related transcripts suggested the emergence of a tolerogenic and immunomodulatory phenotype. Complementary scanning transmission X-ray microscopy and low-energy X-ray fluorescence mapping confirmed substantial nanoparticle internalization and revealed intracellular carbon accumulation, increased oxygen signals, and altered sodium and magnesium distributions, consistent with ionic and membrane perturbations. Collectively, these findings indicate that PE N/MPs might elicit profound metabolic stress in vaginal epithelial cells, including redox disequilibrium and immune modulation, possibly driving them toward an adaptive but inflammation-linked phenotype. While the broader implications for epithelial barrier function and mucosal homeostasis require further validation in more complex models, this study provides a mechanistic framework to explore how environmental polymeric contaminants may influence vaginal epithelial cell physiology.</p>