Disrupting the inflammation-oxidative stress feedback loop via transdermal nanodelivery of Shikonin using a zein/chitosan core-shell platform.

Psoriasis is a chronic inflammatory skin disorder for which effective topical therapy remains challenging due to limited skin penetration and insufficient modulation of the pathological microenvironment. Disease progression is sustained by a self-amplifying loop between inflammation and oxidative stress, largely mediated by hyperactivation of the IL-17A/JAK2/STAT3 signaling pathway. Herein, we report the development of a core-shell nano-delivery system (SKN-ZCNPs) to enhance the transdermal delivery and therapeutic efficacy of Shikonin (SKN), a multi-target anti-inflammatory and antioxidant agent. SKN-ZCNPs were constructed via hydrophobic self-assembly of SKN with zein to form a nanosized core, followed by electrostatic coating with chitosan to confer a positively charged shell. This rational design significantly improved the skin permeability, stability, and sustained release of SKN at psoriatic lesions. Both in vitro and in vivo studies demonstrated that SKN-ZCNPs exhibited superior anti-inflammatory and antioxidant activities compared with free SKN, leading to marked alleviation of psoriasiform symptoms in an imiquimod-induced mouse model. Mechanistically, SKN-ZCNPs effectively disrupted the pathogenic inflammation-oxidative stress cycle by suppressing the IL-17A/JAK2/STAT3 axis, accompanied by attenuation of local and systemic immune activation. Collectively, this naturally derived nano-delivery strategy integrates efficient transdermal transport with multi-pathway regulation, offering a promising and translational approach for the comprehensive topical management of psoriasis.