Berberine‐Mangiferin Self‐Assembled Carrier‐Free Hydrogel Suppresses NETosis for Augmented Psoriasis Treatment

ABSTRACT

Psoriasis therapy is constrained by the poor bioavailability and cutaneous delivery of natural compounds. To address this, we develop an innovative carrier‐free hydrogel (BBR‐MF gel) via molecular co‐assembly of berberine (BBR) and mangiferin (MF). This self‐assembled system forms a stable, shear‐thinning, and self‐healing network driven by π–π stacking and hydrogen bonding, enabling injectable administration and enhances skin retention for synergistic drug delivery. In an imiquimod‐induced murine psoriasis model, topical application of the BBR‐MF gel significantly alleviate clinical and histopathological symptoms, outperforming individual BBR or MF treatments. Transcriptomic analysis revealed potent downregulation of the IL‐17 and NF‐κB signaling pathways. Mechanistically, the gel directly inhibits neutrophil extracellular trap formation (NETosis) and, by altering the neutrophil secretome, subsequently attenuates the activation of NF‐κB and STAT3 pathways in keratinocytes, thereby disrupting a critical pathogenic immune‐epidermal crosstalk. The hydrogel exhibit excellent biocompatibility both in vitro and in vivo. This work presents a safe and effective self‐assembled nanoplatform that not only augments the synergistic efficacy of natural products but also unveiled a multimodal mechanism targeting NETosis and inflammatory signaling, offering a promising translational strategy for psoriasis and related inflammatory diseases.