Title : From polyphenol to precision topical therapy: Resveratrol nanoemulgel modulating HMGB1/NF-κB axis in atopic dermatitis
Abstract:
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction and immune dysregulation. Resveratrol (RES), a polyphenolic compound, has shown promising anti-inflammatory activity; however, its poor aqueous solubility and limited skin delivery restrict its topical therapeutic potential. This study aimed to develop and evaluate a RES-loaded nanoemulgel (RES-NEG) for improved topical delivery and management of AD.
RES-loaded nanoemulsions (RES-NE) containing 0.5%, 0.75%, and 1% w/w RES were prepared by spontaneous nano-emulsification and incorporated into a SEPINEO™ P 600 gel base containing propylene glycol. The formulations were characterized for droplet size, polydispersity index, pH, viscosity, drug content, and stability. Ex vivo skin permeation and retention studies were performed using mouse skin. Skin distribution was assessed using coumarin-6-loaded NEG. Safety was evaluated by skin irritation studies. Therapeutic efficacy was investigated in an 2,4-Dinitrochlorobenzene induced BALB/c AD mouse model through clinical evaluation, histopathology, western blotting, and real-time PCR analysis of inflammatory markers.
The optimized RES NE showed droplet sizes in the range of 180-230 nm with PDI < 0.3, indicating uniform globule distribution. RES-NEGs exhibited pseudoplastic shear-thinning behavior, skin-compatible pH, drug content >90%, and remained stable for three months at room temperature and 2-8 °C. Ex vivo studies demonstrated significantly higher RES retention in mouse skin from RES-NEG compared with free RES gel. Coumarin-6 imaging confirmed enhanced localization in the upper epidermis, while irritation studies showed no signs of erythema or edema. In the AD mouse model, RES-NEG significantly reduced the expression of HMGB1, RAGE, TLR4, and phosphorylated NF-κB. RT-PCR analysis further showed downregulation of key pro inflammatory cytokines, including TSLP, IL-4, IL-13, IL-31, TNF-α, and IL-6, particularly with 1% w/w RES-NEG. Histopathological evaluation confirmed improvement in epidermal integrity with reduced hyperplasia and acanthosis. The therapeutic effect of 1% RES-NEG was comparable to marketed desonide gel(0.05%).
RES-NEG enhanced topical skin retention of resveratrol and effectively attenuated AD associated inflammation through modulation of the HMGB1/RAGE/TLR4/NF-κB pathway. These findings suggest that RES-NEG may represent a promising corticosteroid-sparing topical strategy for AD management.
