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

Abstract

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.