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<p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月3日

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  • Yamei Gao,
  • Xueting Shen,
  • Jiliang Lu,
  • Chaojing Zhou,
  • Shaohu Huo,
  • Ziyue Diao,
  • Chao Chen,
  • Xin Han,
  • Zhiqiang Yin

摘要

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.

Graphical Abstract