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

Summary

Hyaluronic acid–butyrate conjugates, especially 5k-HAB, markedly improved skin retention versus free butyrate by leveraging CD44 overexpression and elevated CES2 in inflamed skin. In a DNFB-induced AD mouse model, 5k-HAB accelerated lesion resolution, restored barrier function, and suppressed inflammation more effectively than HA, free butyrate, or higher-MW conjugates.

Key Findings

• 5k-HAB increased skin retention 6.47-fold versus free butyrate in IVPT using normal and AD-like skin.
• Targeting and release were mediated by CD44 overexpression and elevated CES2 activity in inflamed skin.
• In DNFB-induced AD mice, 5k-HAB reduced TEWL and erythema, restored hydration, and normalized epidermal structure.
• 5k-HAB upregulated barrier proteins, mitigated oxidative stress, and suppressed inflammatory cytokines more than HA, free butyrate, or higher-MW conjugates.

Clinical Implications

Suggests a path toward topical AD treatments that prioritize dermal retention and disease-triggered release, potentially improving efficacy and reducing systemic exposure. Could inform formulation strategies using HA-based targeting.

Limitations

• Preclinical study without human clinical data; translatability to patients remains to be tested.
• Long-term safety, local tolerability, and manufacturing scalability of HAB are not addressed.

Future Directions

Advance to ex vivo human skin and early-phase clinical trials to assess safety, pharmacodynamics, and efficacy; optimize molecular weight and dosing; evaluate combination with standard AD therapies.