Abstract

CD44 and TRPV1 are confirmed to be upregulated in the inflamed skin of atopic dermatitis models. • The dual-targeted VHC carrier enhances intradermal drug retention and residence time. • Cur/VHC achieves selective cytotoxicity in inflamed keratinocytes via dual-receptor targeting. • VHC acts as a competitive TRPV1 antagonist, demonstrating anti-pruritic efficacy in vivo . • Cur/VHC integrates antipruritic, anti-inflammatory, and barrier-repair functions in ISDs. Inflammatory skin diseases (ISDs) involve a vicious cycle of inflammation, pruritus, and tissue damage, posing a persistent therapeutic challenge. To interrupt this cycle, a multifunctional amphiphilic polymer (VHC) is engineered by conjugating hyaluronic acid with octadecylamine and vanillyl alcohol, forming a dual-targeting transdermal nanocarrier. VHC markedly enhances intradermal retention (3.4-fold vs. free Cur at 4 h) and cellular uptake (185-fold vs. free C 6 ) by anchoring to CD44 and TRPV1 receptors, while simultaneously inhibiting TRPV1 activation and expression, a central mediator of itch signaling, to alleviate pruritus. Benefiting from its amphiphilic structure, VHC also functions as an efficient carrier for poorly soluble drugs, broadening its therapeutic scope. Encapsulation of the anti-inflammatory agent curcumin (Cur) yields Cur/VHC micelles (~240 nm) with sustained release under mildly acidic conditions. Because CD44 and TRPV1 are overexpressed under inflammatory conditions, Cur/VHC preferentially accumulates in TNF-α-stimulated HaCaT cells, suppresses pathological proliferation, and mitigates oxidative stress. In an atopic dermatitis mouse model, topical VHC and Cur/VHC accelerate inflammation resolution, normalize epidermal architecture, restore barrier proteins (K10 and filaggrin), relieve itch (by reducing IL-31, IgE, and tachykinin precursor 1), promote hair follicle regeneration, and reduce mast cell degranulation. By integrating receptor targeting, TRPV1 inhibition, and anti