Hydroxypropyl-β-cyclodextrin co-delivery hydrogel of crisaborole and curcumin for combinational antioxidant/anti-inflammatory therapy of vitiligo

Vitiligo is a depigmenting autoimmune disease driven by oxidative stress and immune-mediated melanocyte destruction. Current therapies are limited by poor drug permeability, systemic side effects, and insufficient efficacy. Herein, we developed a novel carbomer-based hydroxypropyl-β-cyclodextrin-encapsulated crisaborole/curcumin hydrogel (Cri/Cur@CD-Gel) for combinational transdermal intervention of vitiligo via dual antioxidant and anti-inflammatory pathways. Hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complexation overcame the inherent hydrophobicity of crisaborole (Cri) and curcumin (Cur), significantly enhancing their aqueous solubility, stability, and transdermal permeability. Leveraging its skin-adhesive properties, the carbomer hydrogel matrix enhanced drug retention and enabled sustained release at lesion sites, thereby improving drug bioavailability. <i>In vitro</i>, Cri/Cur@CD, leveraging the solubilizing power of HP-β-CD, restored melanocyte viability under oxidative stress, scavenged ROS, normalized mitochondrial membrane potential, and elevated cAMP levels to enhance melanogenesis and tyrosinase activity. <i>In vivo</i>, Cri/Cur@CD-Gel achieved significant repigmentation in monobenzone-induced vitiligo mice, markedly reducing epidermal ROS, CD8⁺ T-cell infiltration, and inflammatory cytokines (TNF-α, IL-1β, and IL-6). This study demonstrates that the combination of HP-β-CD-based encapsulation and carbomer hydrogel delivery serves as a potential topical administration platform for co-delivering hydrophobic crisaborole and curcumin, and establishes a promising strategy to alleviate vitiligo, that concurrently addresses oxidative damage, inflammatory responses, and melanocyte regeneration.