Hyaluronic acid-butyrate conjugates for barrier restoration in atopic dermatitis: CD44-mediated retention and inflammation-responsive release.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by barrier dysfunction, immune dysregulation, and oxidative stress. Effective therapy requires strategies that improve local drug retention while addressing both inflammation and barrier repair. In this study, hyaluronic acid-butyrate (HAB) conjugates with different molecular weights were synthesized and evaluated as dual-functional therapeutics for AD. IVPT using normal and AD-like skin demonstrated that HAB, particularly 5 k-HAB, achieved superior penetration and markedly enhanced skin retention (6.47-fold) compared with free butyrate. These improvements were attributed to inflammation-responsive mechanisms: CD44 overexpression in diseased skin, which promotes HA-mediated targeting, and elevated CES2 activity, which triggers local butyrate release. In a DNFB-induced mouse model, 5 k-HAB significantly accelerated lesion resolution, reduced trans-epidermal water loss and erythema, restored hydration, and normalized epidermal structure. Mechanistic studies revealed that 5 k-HAB synergistically promotes keratinocyte proliferation, mitigates oxidative stress, upregulates key barrier proteins, and suppresses inflammatory cytokines more effectively than HA, free butyrate, or higher-MW conjugates. These results highlight the critical importance of using disease-relevant skin models for evaluating dermal drug delivery and show that enhancing local retention is more impactful than penetration alone. Collectively, 5 k-HAB demonstrates a rational, multifunctional approach for targeted transdermal therapy of AD and other inflammatory skin disorders.