Zinc oxide nanoparticles exacerbate allergic skin inflammation via T cell dysregulation and enhancement of immune cell infiltration

Zinc oxide nanoparticles (ZnO NPs) are widely used in consumer and biomedical products due to their antimicrobial activity and favorable biocompatibility. Although dermal exposure to ZnO NPs is generally considered safe, penetration beyond the skin barrier may occur under inflammatory or barrier-compromised conditions. However, the immunotoxicological consequences of ZnO NP exposure, particularly their effects on adaptive immune regulation during allergic inflammation, remain incompletely understood. Using ovalbumin (OVA)-induced murine models of delayed-type hypersensitivity (DTH) and atopic dermatitis (AD), we demonstrated that the immunomodulatory effects of ZnO NPs were highly dependent on the route of exposure. Among pharyngeal aspiration, intravenous, and subcutaneous administration, only subcutaneous exposure significantly exacerbated antigen-driven cutaneous inflammation. In both models, ZnO NPs treatment enhanced immune cell infiltration, promoted mast cell degranulation, and amplified antigen-specific humoral responses. Notably, ZnO NPs markedly increased CD4 + T cell accumulation in inflamed skin without altering intrinsic cytokine polarization. Mechanistically, ZnO NPs released Zn²⁺ ions, leading to intracellular reactive oxygen species (ROS) generation in T cells and subsequent activation of NF-κB (p65), p38, and c-Jun N-terminal kinase (JNK) signaling pathways. This ROS-dependent signaling cascade upregulated the skin-homing chemokine receptors C-C motif chemokine receptor 4 (CCR4), CCR8, and CCR10. Consistent with these changes, ZnO NP-treated T cells exhibited enhanced chemokine-directed migration in vitro. These findings demonstrate that subcutaneous exposure to ZnO NPs promotes local immune alterations in allergic skin, characterized by increased inflammatory cell infiltration and accumulation of CD4 + T cells. ZnO NP-derived Zn²⁺ induces ROS-dependent activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling, leading to the upregulation of skin-homing chemokine receptors. Together with the enhanced chemokine-directed migration observed in vitro, these findings indicate that ZnO NP exposure alters T cell homing-related responses. These homing-related alterations represent an underappreciated aspect of nanoparticle immunotoxicity and highlight the need to consider tissue-specific immune dynamics when assessing the safety of ZnO NPs, particularly under conditions of skin inflammation or barrier disruption.