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

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.