Distinct Skin Penetration and Immune Responses to Ionic and Nanoparticulate Cobalt in Allergic Contact Dermatitis

ABSTRACT Background Cobalt is a well‐established cause of allergic contact dermatitis (ACD), but data on the skin absorption, toxicity, and immunological effects of cobalt nanoparticles (CoNPs) remain limited. Given the increasing use of nanomaterials in industry and medicine, understanding how cobalt speciation affects skin immune activation is of growing clinical relevance. Methods Fourteen cobalt‐allergic individuals underwent standardized patch testing with cobalt chloride (CoCl 2 ) and CoNPs at equivalent nominal doses. Skin biopsies from positive reactions were analyzed by RNA sequencing to characterize immune and barrier‐related pathways. Cobalt penetration and localization were further examined in reconstructed and ex vivo human skin models using inductively coupled plasma mass spectrometry (ICP‐MS) and laser ablation ICP‐TOFMS imaging. Results Both CoCl 2 and CoNPs elicited positive patch test reactions, although CoNP responses were delayed and milder. CoCl 2 also demonstrated a clearer dose‐dependent increase in clinical reactivity, whereas CoNP responses were comparatively stable across concentrations. Transcriptomic profiling revealed substantial overlap between exposures, with reaction strength emerging as the main determinant of gene expression changes. Increasing severity was associated with enrichment of interferon signaling, inflammatory response, apoptosis, cell cycle‐related programs, and glycolysis in both exposures. Lipid metabolic pathways were significantly associated with reaction strength in CoCl 2 ‐exposed skin but not in CoNP ‐exposed samples. Direct comparison using a paired DESeq2 design identified 281 differentially expressed genes between CoCl 2 and CoNP . Functional enrichment of these genes revealed distinct biological signatures between exposures, including upregulated interferon and antiviral pathways and downregulated epithelial differentiation programs in CoCl 2 compared to CoNP . In complementary skin models, CoCl 2 exhibited deeper penetration, higher trans‐epidermal flux, and broader intracellular accumulation across epidermal and dermal cell populations, whereas CoNPs remained largely confined to the stratum corneum and adnexal structures. Conclusions Cobalt‐induced ACD is shaped by both reaction strength and cobalt speciation. While CoCl 2 and CoNPs share a core interferon‐driven inflammatory program that scales with clinical severity, ionic cobalt penetrates more deeply and preferentially engages interferon and antiviral pathways in dermal compartments, whereas CoNPs are retained more superficially and are associated with epithelial differentiation programs. These findings underscore the importance of chemical form, tissue penetration, bioavailability, and retention in determining immune responses and dermal hazard of cobalt and other metal nanomaterials.