Quercetin-loaded cellulose nanocrystals for targeted redox modulation and inflammation control in rosacea therapy via the SOD2-NF-κB pathway.

Quercetin-loaded cellulose nanocrystals (QL-CNC) were developed as a reactive oxygen species (ROS)-responsive nanocarrier for the targeted treatment of rosacea. A murine model of rosacea-like dermatitis was induced using LL-37. The therapeutic efficacy of QL-CNC was systematically evaluated through clinical erythema assessment, histopathological analysis, mast cell staining, and quantification of proinflammatory cytokines (IL-6, TNF-α, IL-1β). Immune polarization was evaluated by analyzing Th1/Th17 responses. To elucidate the underlying mechanism, mitochondrial antioxidant defense was assessed, including SOD2 translocation and activity, ROS scavenging capacity, and NF-κB activation. The specific involvement of NF-κB was verified using the activator NFA1. Additional in vitro studies using HaCaT keratinocytes corroborated the anti-inflammatory and antioxidant effects. Biocompatibility and systemic toxicity were also thoroughly evaluated. QL-CNC treatment markedly alleviated LL-37-induced rosacea-like inflammation, reducing erythema, inflammatory infiltration, mast cell activation, and proinflammatory cytokine expression. It also suppressed Th1/Th17 immune polarization. Mechanistically, QL-CNC enhanced mitochondrial antioxidant defense by facilitating SOD2 translocation and activation, effectively scavenged ROS, and inhibited NF-κB activation-as indicated by reduced p65 phosphorylation and nuclear translocation. The therapeutic effects were abolished upon NF-κB activation with NFA1, confirming the critical role of this pathway. In HaCaT cells, QL-CNC significantly mitigated LL-37-induced inflammatory responses and oxidative stress. The nanocrystal system exhibited excellent biocompatibility with no detectable systemic toxicity. These findings indicate QL-CNC represents an effective redox-based nanotherapeutic strategy that concurrently targets oxidative stress and inflammation via modulation of the SOD2-NF-κB axis, offering promising potential for controlled anti-inflammatory therapy in rosacea and other inflammatory skin diseases.