A Therapeutic Copper Hydrogel for Seborrheic Dermatitis: From Fungal Eradication to Skin Lesion Repair

Seborrheic dermatitis (SD) is a chronic relapsing inflammatory dermatosis closely associated with Malassezia furfur overgrowth. Given the growing interest in metal-based antimicrobials, copper compounds were investigated here as potential anti-Malassezia agents for SD treatment. CuSO₄ showed the strongest antifungal activity against M. furfur at 1 mM and rapidly reduced fungal viability. Mechanistic analyses revealed intracellular copper accumulation, elevated Fe²⁺ levels, increased reactive oxygen species generation, and enhanced lipid peroxidation, collectively suggesting an oxidative damage pattern with ferroptosis-like features. Based on its potent anti-Malassezia activity, a CuSO₄-loaded xanthan gum/hyaluronic acid hydrogel (HG-Cu) was further developed for integrated local treatment of seborrheic dermatitis. HG-Cu exhibited viscous-flow behavior, high structural stability, and favorable biocompatibility. In a guinea pig model of M. furfur-induced seborrheic dermatitis, HG-Cu effectively suppressed fungal proliferation in lesions through sustained copper release. Histopathological analysis showed that HG-Cu markedly ameliorated skin lesions, reduced inflammatory infiltration, and promoted matrix reconstruction and skin repair by upregulating type III collagen (COL III) at the early stage and enhancing type I collagen (COL I) deposition at the later stage. Taken together, HG-Cu offers a promising localized therapeutic approach for seborrheic dermatitis by integrating sustained antifungal activity, inflammation control, and skin barrier restoration.