Synergistic remodeling of psoriatic immune niche via ginsenoside CK/tofacitinib co-loaded dermal targeting transfersomes.

Effective topical management of psoriasis is significantly hindered by the robust stratum corneum barrier and the complex inflammatory network residing in the dermis. To overcome these challenges, we developed a novel transfersomes (TFs) - based delivery system for the co-delivery of Ginsenoside CK (CK) and JAK inhibitor Tofacitinib (TOF). Uniquely, CK was employed to substitute cholesterol in the lipid bilayer. This design leveraged the unique pharmacological and structural properties of CK to modulate membrane properties while functioning as a potent immune regulator. The optimized TFs exhibited a uniform nanosize and exceptional deformability, enabling them to squeeze through the skin barrier and achieve superior drug deposition in deep dermal layers compared to conventional controls. This co-delivery strategy demonstrated remarkable therapeutic efficacy, significantly alleviating erythema and scaling while drastically reducing the thickening of the stratum corneum and Severity Index (PASI) scores in psoriatic mouse model. Distinct from conventional treatments, mechanistic evaluations revealed that the system synergistically remodeled the immune microenvironment. In psoriasis recurrence model, the co-delivery system significantly mitigated the re-activated cutaneous immune responses. It effectively blocked the JAK/STAT signaling pathway and suppressed the infiltration of key pathogenic cells, including IL-17 A+ T cells, Langerhans cells, effector memory T-cells and tissue-resident T cells, which are notoriously difficult to target topically. Furthermore, CK potentiated the activity of TOF, leading to a marked reduction of IL-17 and upregulation of IL-10. These findings suggest that CK/TOF-co-loaded TFs represent a promising strategy for targeted psoriasis immunotherapy, leveraging nanocarrier-mediated permeation to significantly inhibit deep-seated dermal inflammation.