Hou Lin, Wang Ning, Miao Qiannan, Wang Zhihua, Yan Fei
Department of Dermatology and Venereology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China.
Acta Biomater. 2025 Jul 1;201:591-603. doi: 10.1016/j.actbio.2025.05.067. Epub 2025 Jun 1.
Psoriasis is an inflammatory skin disease characterized by keratinocyte hyperproliferation and immune cell infiltration. The IL-17 signaling in Th17 cells is crucial in the pathogenesis of psoriasis. Epigenetic regulation could modulate the IL-17 signaling pathway. However, no effective epigenetic drugs can specifically target IL-17 in Th17 cells for psoriasis treatment. Herein, a CD4T cell biomimetic nanoplatform (HMDC4M) was synthesized for improved dual epigenetic therapy through synergistic suppression of the IL-17 pathway in psoriasis. HMDC4M used hollow mesoporous silica as a framework to load two epigenetic drugs, decitabine and SGCCBP30. HMDC4M exhibited skin absorption capability and selectivity to Th17 cells by coating with CD4T cell membrane. Moreover, HMDC4M could competitively bind with IL-23, preventing its interaction with CD4T cells. This inhibited the differentiation of CD4T cells into Th17 cells and suppressed the production of the inflammatory cytokine IL-17. The cell membrane function of HMDC4M synergized with DNA demethylation and histone deacetylation activities, inhibiting Th17 growth. Finally, the therapeutic effects of HMDC4M were validated in an IMQ-induced psoriasis mouse model. HMDC4M significantly inhibited the PASI score, epidermal thickness, hyperplasia, and splenomegaly. This study provided a proof of concept of biomimetic nanoplatform-based nano epigenetic therapy for inflammatory disease, with great promise to achieve superior clinical outcomes. STATEMENT OF SIGNIFICANCE: 1. A CD4+ T cell biomimetic nanoplatform (HMDC4M) was developed. 2 HMDC4M could competitively bind with IL-23, preventing its interaction with CD4+ T cells. 3 HMDC4M could enhance dual epigenetic therapy for targeting Th17 cells in Psoriasis. 4 HMDC4M significantly inhibited the PASI score, epidermal thickness, hyperplasia, and splenomegaly in an IMQ-induced psoriasis mouse model.
银屑病是一种以角质形成细胞过度增殖和免疫细胞浸润为特征的炎症性皮肤病。Th17细胞中的白细胞介素17（IL-17）信号传导在银屑病的发病机制中至关重要。表观遗传调控可调节IL-17信号通路。然而，目前尚无有效的表观遗传药物能够特异性靶向Th17细胞中的IL-17用于银屑病治疗。在此，合成了一种CD4T细胞仿生纳米平台（HMDC4M），通过协同抑制银屑病中的IL-17通路来改善双重表观遗传治疗。HMDC4M以中空介孔二氧化硅为骨架，负载两种表观遗传药物，地西他滨和SGCCBP30。HMDC4M通过包被CD4T细胞膜表现出皮肤吸收能力和对Th17细胞的选择性。此外，HMDC4M可以与IL-23竞争性结合，阻止其与CD4T细胞相互作用。这抑制了CD4T细胞向Th17细胞的分化，并抑制了炎性细胞因子IL-17的产生。HMDC4M的细胞膜功能与DNA去甲基化和组蛋白去乙酰化活性协同作用，抑制Th17细胞生长。最后，在咪喹莫特诱导的银屑病小鼠模型中验证了HMDC4M的治疗效果。HMDC4M显著抑制了银屑病面积和严重程度指数（PASI）评分、表皮厚度、增生和脾肿大。本研究为基于仿生纳米平台的纳米表观遗传治疗炎症性疾病提供了概念验证，有望实现卓越的临床疗效。重要意义声明：1. 开发了一种CD4+T细胞仿生纳米平台（HMDC4M）。2. HMDC4M可以与IL-23竞争性结合，阻止其与CD4+T细胞相互作用。3. HMDC4M可以增强针对银屑病中Th17细胞的双重表观遗传治疗。4. 在咪喹莫特诱导的银屑病小鼠模型中，HMDC4M显著抑制了PASI评分、表皮厚度、增生和脾肿大。
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