Quercetin-zinc based metal-phenolic networks ameliorate psoriasis by rebalancing the microbiota-immune-epidermis homeostasis.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulated immune responses and impaired skin barrier function. Despite available treatments, challenges such as systemic side effects, tolerance, and economic burdens in some patients remain. This study developed a quercetin‑zinc networks (QU-Zn) using a facile metal-phenolic network self-assembly strategy for the topical treatment of psoriasis. The synthesized QU-Zn exhibited irregular sphere-like morphology, excellent water dispersibility and stability. QU-Zn demonstrated potent free radical scavenging capacity in vitro, as well as strong anti-inflammatory effects. QU-Zn application in the living animals markedly alleviated imiquimod (IMQ)-induced psoriasis-like inflammation and epidermal hyperplasia, and it also prevented the disease relapse. Mechanistically, RNA sequencing and validation experiments revealed that QU-Zn suppressed the proinflammatory macrophage/Th17 cell axis and downregulated the phosphorylation of STAT3. Additionally, QU-Zn exhibited strong antibacterial activity against Staphylococcus aureus, including disruption of bacterial membranes and inhibition of biofilm formation, thereby addressing microbial dysregulation in psoriasis. In conclusion, QU-Zn exerted enhanced therapeutic effects against psoriasis through immunomodulatory, antioxidant, anti-inflammatory, and antimicrobial activities, helping to rebalance the "microbiota-immune-epidermis" homeostasis and offering a promising nanotherapeutic strategy for psoriasis management.