A combination therapy strategy: precision co-targeting of CCR7 and JAK1 with a smart hydrogel for inflammatory skin diseases.

Inflammatory skin diseases (ISDs) pose a major global burden, yet current therapies are limited by efficacy, accessibility, and cost, necessitating novel effective treatments. Thus, our study proposes a novel synergistic therapeutic strategy for psoriasis (PSO) and atopic dermatitis (AD) by concurrently targeting two critical pathological axes: immune cell chemotaxis via CCR7 inhibition and local inflammatory signaling via JAK1 suppression. A pH-responsive hydrogel (C-P@U/C-siCCR7) was designed for co-delivery of CCR7-targeting siRNA and the JAK1 inhibitor upadacitinib (UPA). Multi-omics analysis confirmed specific CCR7 overexpression in patient and model tissues. In vitro, the system inhibited keratinocyte proliferation, induced apoptosis, and downregulated key proteins in the JAK-STAT and PI3K/AKT/mTOR pathways along with pro-inflammatory cytokines. In IMQ-induced PSO and DNCB-induced AD mouse models, topical hydrogel application ameliorated skin lesions, restored the epidermal barrier, reduced hyperplasia and infiltration, and alleviated systemic immune activation-including suppression of splenomegaly and serum cytokines (IL17A, TNFα, IL4, IL13)-with favorable biosafety. The therapeutic effects were mechanistically linked to synergistic downregulation of CCR7, JAK1, STAT3, and mTOR in lesions, and reduced populations of aberrantly activated T cells, neutrophils, and dendritic cells in the spleen. This work provides a novel delivery platform and experimental evidence for developing effective, precise topical combination therapies against ISDs.