Targeted dermal delivery of phloretin via thermoresponsive nanoparticles potently suppresses STAT3/NF-κB-driven psoriatic inflammation

Background: Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Although the natural flavonoid Phloretin (Phl) shows anti-inflammatory potential, its poor bioavailability limits its therapeutic use.

Purpose: This study aimed to elucidate the antipsoriatic mechanism of Phl and develop a targeted, thermoresponsive nanodelivery system to enhance its efficacy for topical treatment.

Methods: The therapeutic effects of Phl were assessed in an imiquimod (IMQ)-induced psoriasis mouse model. Network pharmacology, molecular docking, and molecular dynamics simulations were used to predict and verify the binding stability of Phl with its potential targets. Quantitative proteomics was conducted to provide a global view of the proteomic shifts and affected pathways. These results were validated in vivo and in cytokine-stimulated HaCaT keratinocytes using western blotting, RT-qPCR, and immunofluorescence. Phl-loaded thermoresponsive phase-change material nanoparticles (PCM-Phl) were synthesized, characterized, and evaluated both in vitro and in vivo.

Results: Phl administration significantly ameliorated erythema, scaling, and epidermal hyperplasia in psoriatic mice. This effect was mediated through the concurrent inhibition of the STAT3 and NF-κB signaling pathways, which suppressed keratinocyte hyperproliferation, aberrant differentiation, and proinflammatory cytokine expression. The PCM-Phl formulation prolonged drug retention at the lesion site, triggered by the inherent hyperthermia of psoriatic lesions and near-infrared irradiation, and demonstrated superior therapeutic outcomes compared to free Phl, achieving a more profound and sustained inhibition of the target pathways.

Conclusion: This study identified dual inhibition of STAT3 and NF-κB as key mechanisms for the antipsoriatic activity of Phl. Furthermore, it presents a promising thermoresponsive nanodelivery strategy that overcomes the biopharmaceutical barriers of Phl, offering a novel approach for topical treatment of psoriasis.