Ursolic acid-loaded bioactive nanoagents alleviate DNCB-induced atopic dermatitis symptoms by facilitating autophagy and antioxidant defenses.

Impaired skin barrier function is a major hallmark of atopic dermatitis (AD). This barrier disruption is driven by the combined effects of autophagy deficiency and excessive reactive oxygen species (ROS) accumulation. Herein, we developed a bifunctional nanoagent (PU) engineered by encapsulating the autophagy-inducing natural compound ursolic acid within the antioxidative hollow mesoporous Prussian blue nanoparticles, and further revealed its multi-network regulatory mechanisms in AD treatment. Mechanistically, PU facilitated the nuclear translocation of ‌transcription factor EB (TFEB) by regulating the AMPK-mTORC1-TFEB signaling axis, promoting the autophagic flux in HaCaT keratinocytes. Furthermore, PU with ROS scavenging activity enhanced endogenous antioxidant defense by activating the Keap1-Nrf2-HO-1 pathway in HaCaT keratinocytes. In DNCB-induced AD mouse model, subcutaneous injection of PU not only promoted tight junction proteins expression, but also repaired the skin barrier function. Ultimately, PU alleviated AD-like symptoms, including inflammatory infiltration and scratching behavior in AD mouse models. This work highlights the potential of bioactive nanoagents loaded with natural compounds to coordinate autophagy activation and antioxidant defense, representing a comprehensive approach for AD treatment.