A Follicle‐Targeting Dual Anti‐Fungal and Immunomodulatory Platform Against Fungal Invasion and Relapse Prevention

Colonization of commensal fungi, particularly Malassezia, and immune-cell recruitment, are two essential drivers initiating processes in dermatitis, which necessitates interventions to prevent skin barrier damage and immune hyperactivation. Herein, we construct theabrownin-selenium nanoparticles (TB-Se NPs) as a dual-function antifungal and immunomodulatory platform with pronounced hair-follicle penetration for counteracting Malassezia-induced dermatitis and recurrence. TB-Se NPs are stabilized by conjugated biomacromolecules from tea-derived polymer TB, yielding reduced size and enhanced stability. Mechanistically, covalent O═C─O bonding between TB-Se NPs and cell walls boosts surface adsorption sixfold compared to bare Se NPs. This interaction disrupts fungal envelope integrity and facilitates a "Trojan Horse" effect, promoting the release of selenols via thiol exchange and interfering with sulfur-related metabolism to induce fungal death. In a Malassezia-induced dermatitis model, follicle-targeted TB-Se NPs suppressed dermatitis phenotypes by restraint on fungal overgrowth and prevention of abnormal keratinocyte proliferation. TB-Se NPs also interfered with neutrophil adhesion and migration capacities and local amplification of the inflammatory response. A Long-term firewall against fungi recurrence has been established by TB-Se NPs, which pre-activate CD4+ T cells and memory T cells to strengthen the immune memory response. Collectively, TB-Se NPs represent a dual-function antifungal and immunomodulatory therapeutic strategy for preventing fungal-induced dermatitis and relapse.