Hyaluronic acid-baicalin conjugate for CD44-Targeted topical therapy of atopic dermatitis with enhanced skin retention and barrier restoration

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, oxidative stress, and epidermal barrier dysfunction. Current therapies often provide incomplete long-term control and may cause adverse effects. Baicalin (BAI), a natural flavonoid with potent anti-inflammatory and antioxidant activities, is a promising candidate for AD treatment; however, its topical application is limited by poor solubility, weak skin penetration, and insufficient retention. To address these challenges, we developed a hyaluronic acid-baicalin conjugate (HA-BAI) that combines enhanced aqueous dispersibility with CD44-associated targeting and intrinsic barrier-supportive properties. HA-BAI exhibited excellent aqueous dispersibility (>220 mg/mL) across different formulation media, whereas free BAI remained poorly soluble (∼0.05 mg/mL). In vitro , HA-BAI exhibited excellent cytocompatibility, suppressed nitric oxide and pro-inflammatory cytokines, enhanced IL-10 expression, and promoted barrier-related proteins in keratinocytes. Ex vivo permeation studies demonstrated enhanced skin accumulation and prolonged retention, with 3.28-fold greater skin-associated fluorescence than the free fluorescent probe at 12 h. In a DNFB-induced AD mouse model, HA-BAI markedly alleviated dermatitis severity, reduced splenomegaly, improved histopathological features, and restored epidermal barrier homeostasis, showing superior therapeutic performance compared with the dose-normalized HA and BAI physical mixture. Collectively, HA-BAI represents a bioactive macromolecular platform that integrates targeted delivery with intrinsic therapeutic functionality for localized treatment of AD. Download: Download high-res image (409KB) Download: Download full-size image