A Novel pH‐Responsive Baicalein@Chitosan Hydrogel for the Topical Treatment of Herpes Simplex Virus Type 1 Skin Infections: Therapeutic Potential and Mechanisms

Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen primarily transmitted through skin-to-skin contact. Traditional antiviral drugs like acyclovir (ACV) have limitations due to viral resistance and side effects, necessitating the development of alternative therapeutic strategies. Drug-loaded hydrogels have emerged as a promising approach for managing various skin infections. Considering the low-pH microenvironment following HSV-1 infection, a pH-responsive baicalein@chitosan (B@C) hydrogel is developed for the topical treatment of HSV-1 skin infections. This hydrogel is synthesized by incorporating baicalein, a natural flavonoid, into a chitosan matrix modified with 4-formylphenylboronic acid and protocatechualdehyde to achieve potent anti-HSV-1 activity and pH-responsiveness. In vitro results demonstrated the hydrogel's pH-dependent inhibitory effect on HSV-1 infections, including ACV-resistant strains. Subsequent investigations confirmed its efficacy in multiple murine infection models. Mechanistically, the B@C hydrogel inhibited viral replication by modulating the phosphorylation of inhibitor of nuclear factor kappa-B kinase subunit beta, promoted collagen synthesis, and decreased reactive oxygen species generation. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis revealed a sustained release of baicalein from the hydrogel, ensuring long-term drug retention in HSV-1-infected skin tissues. Collectively, these findings suggest that the B@C hydrogel holds significant potential for the therapeutic management of HSV-1 skin infections.