中文摘要

第一部分 TYK2基因在银屑病中的致病机制及治疗靶点探究

背景：银屑病（Psoriasis）一种以免疫异常为特征的慢性复发性皮肤疾病，其致病机制涉及遗传易感性、环境诱因及免疫调节失衡等多维度的因素。在相关免疫信号传导网络中，Janus激酶-信号转导和转录激活因子（Janus Kinase-Signal Transducer and Activator of Transcription, JAK-STAT）通路起到重要的调控作用，通过介导多种细胞因子的跨膜信号传递，对免疫细胞的增殖分化、迁移及其功能发挥重要作用。该通路的异常激活与包括银屑病在内的多种自身免疫性疾病密切相关。酪氨酸激酶2（Tyrosine Kinase 2, TYK2）作为关键成员，参与调控银屑病炎症级联反应的核心环节。近年来，TYK2抑制剂显示出在银屑病治疗中的潜力，但对其皮肤局部免疫中的分子互作机制仍需系统性探究。

目的：本研究旨在深入探讨TYK2基因在银屑病发病中的机制作用，以及作为治疗靶点的潜力及可能问题，为开发对应的新型治疗策略提供科学依据。

方法：本研究整合了多个银屑病皮损转录组学数据集，包括GSE30999、GSE78097和GSE117239等，通过差异基因表达分析、加权基因共表达网络分析（Weighted Gene Co-expression Network Analysis, WGCNA）、基因共表达相关性分析、基因集富集分析（Gene Set Enrichment Analysis, GSEA）、蛋白互作网络分析（protein-protein interaction，PPI）以及单细胞转录组数据整合等方法，分析TYK2基因的差异性表达及其在银屑病皮损中的致病机制。此外，我们基于GTEx单细胞测序结果对TYK2基因在多器官和多细胞类型中的表达特征分析，并且借助银屑病大规模全基因组关联研究（Genome-Wide Association Study，GWAS）结果和PrediXcan方法推断银屑病患者各个组织中的TYK2基因表达量，使用SMR方法验证了TYK2基因的泛疾病关联。

结果：研究发现TYK2基因在银屑病皮损组织中的表达显著高于非皮损组织，且与多个关键银屑病相关基因，如白介素-17受体A（Interleukin-17 Receptor A, IL17RA）、IFNAR2、STAT3/4、JAK1、IL10RB、IL4R、MYC等存在显著共表达关系。TYK2的共表达基因显著富集于IL-17、IL-22信号通路以及I型干扰素（Type I Interferon, IFN）信号通路。PPI分析显示TYK2周围关联了多个免疫信号关键蛋白，如 IL17RA、IFNAR1/2、IL10RB、STAT2、SOCS1等，在IL-23/IL-17 信号通路、Th17相关免疫应答、JAK-STAT信号通路、I 型IFN信号通路、PI3K-Akt 信号通路等中富集。TYK2基因在淋巴细胞等不同细胞类型中呈现泛细胞表达模式。此外，TYK2基因的表达不局限于皮肤，还在脑、肝等组织中具有较高的表达水平，显示出泛系统表达和泛疾病关联的特征。

结论： TYK2基因在银屑病的发病机制中起到重要作用，通过与 IL-17、IL-22等信号通路的复杂互作，可同时参与免疫与代谢调控。TYK2基因的泛器官组织的表达模式提示，局部经皮递送TYK2抑制剂有望减少系统暴露导致的全身副作用，从而为银屑病的精准化治疗开辟新方向。

第二部分 基于TYK2抑制剂的双重释放自锁微针贴片的制备与性能表征

背景：银屑病是一种以角质形成细胞异常增殖和免疫调节异常为特征的慢性炎症性皮肤病。传统口服药物存在系统性毒副作用，而新型TYK2抑制剂Deucravacitinib（Deu）虽对银屑病有明显疗效，但也存在相关系统副作用。本研究前期结果进一步表明，TYK2基因在正常人群及银屑病人群中存在泛器官泛细胞的表达模式，因此，经皮递送TYK2抑制剂有望减少全身性副作用，打破系统给药对剂量的制约，然而目前Deu尚无可用的经皮给药策略。卡泊三醇（Calcipotriol, Cal）是一种维生素D₃衍生物，作为银屑病的经典外用药物，常配合系统药物同时治疗，能够抑制角质形成细胞增殖并促进终末分化，Cal封包治疗可显著减轻皮损肥厚程度，促进药物渗透，因此可以作为TYK2抑制剂经皮给药的对比及联合应用药物。

目的：本研究旨在对TYK2抑制剂采取经皮递送方式给药，充分发挥Deu局部靶向治疗特性；并构建基于TYK2抑制剂的双重释放自锁微针贴片（Deu@Cal MN），同时实现TYK2抑制剂Deu的瞬时释放与Cal的缓慢持续释放，并在后续研究中比较Deu经皮给药策略与传统Cal给药的疗效差异。

方法：本研究采用模板真空填充法，构建以聚乙烯醇（Polyvinyl Alcohol, PVA）为内环材料、甲基丙烯酸化透明质酸（Methacrylated Hyaluronic Acid, HAMA）为外环和背衬层材料的Deu@Cal微针贴片。双重释放的微针内环PVA针尖溶解一次性释放Deu，HAMA外环和背衬层缓慢释放Cal, 且外环溶胀形成机械互锁结构，以增强微针贴片的粘附性。研究从材料合成与表征、HAMA溶胀性能与微观结构观察、力学性能测试、药物分布与控释行为（体外Franz扩散池与体内荧光成像）、生物相容性评估（细胞毒性、溶血反应）等方面系统开展性能验证。

结果：研究结果表明，该微针贴片具备优异的机械强度和力学性能，能够有效穿透角质层完成给药。Deu@Cal微针的HAMA外环具有> 650%的快速膨胀能力，形成稳定的机械互锁结构，交联后微针的黏附力显著增强。药物体内荧光追踪显示，Deu在PVA内环针尖刺入后可迅速溶解并快速吸收入皮肤内，而Cal可在皮肤表面维持稳定的荧光信号，证实具备持续缓慢释放的能力。生物相容性评估显示微针几乎无溶血反应且对成纤维细胞无毒性，插入后的皮肤微孔可在2小时内愈合。

结论：本研究创新性地开发了TYK2抑制剂Deu的经皮给药策略，并研发了基于Deu的双重释放自锁微针贴片（Deu@Cal MN），可同时实现PVA内环Deu的快速释放与HAMA外环及背衬层Cal的缓慢释放，局部靶向肥厚性皮损，并降低了Deu系统暴露的副作用风险。该微针贴片展现出良好的力学性能、生物相容性和安全性，为今后银屑病以及其他慢性皮肤病的精准治疗提供了新型药物递送策略。

第三部分 基于TYK2抑制剂的双重释放自锁微针贴片治疗小鼠银屑病样皮损的疗效和安全性研究

背景：银屑病常伴有角质形成细胞异常增殖和免疫失调，TYK2抑制剂Deucravacitinib（Deu）在系统治疗中显示出良好疗效，而前期研究表明，TYK2基因具有泛器官组织的表达特性，存在潜在系统不良反应；此外部分银屑病患者在口服Deu后，仍有局部顽固性肥厚性皮损，提示需进一步优化局部治疗策略。前期研究开发了基于TYK2抑制剂的经皮递送微针（Deu@Cal MN），证实其具有良好的力学性能及黏附性、药物递送效率及生物相容性。本研究旨在进一步评估该经皮给药策略在小鼠银屑病模型中的疗效和安全性，明确对局部皮损增殖及免疫调节的能力。

目的：将基于Deu的经皮递送策略应用于咪喹莫特诱导的小鼠银屑病样皮损，比较Deu经皮给药策略与传统Cal给药的治疗效果，并探讨Deu@Cal联合自锁微针贴片在咪喹莫特诱导的小鼠银屑病样皮损中的治疗效果及安全性，评估在抑制角质形成细胞增殖、调节局部与系统免疫方面的作用机制。

方法：建立BALB/c小鼠银屑病模型，连续8天外用咪喹莫特乳膏诱导皮损，自第3天起局部给予不同类型微针贴片治疗，分为空白对照组、模型组、空白微针组、Cal MN组、Deu MN组及Deu@Cal MN组。通过皮损拍照及改良PASI评分评估整体银屑病严重程度。通过皮肤厚度测量、皮肤组织病理H&E染色、免疫荧光染色检测Ki67表达来评估皮肤增殖情况。对银屑病相关炎症因子（IL-6、IL-17、IL-23、TNF-α等）的表达水平进行皮肤组织qRT-PCR及免疫组化染色分析。此外，本研究还评估了脾脏指数并采用流式细胞术分析脾脏Th17细胞比例。最后对各治疗组小鼠的主要脏器进行组织学分析以评估治疗的安全性。

结果：Deu MN治疗组的整体治疗效果与Cal MN治疗组相当，治疗5天后即见皮肤红斑、鳞屑及浸润缓解且PASI总体评分明显降低， Deu@Cal MN治疗组皮损缓解最明显。表皮厚度（ETmin、ETmax）、Ki67阳性率及组织病理学结果表明，Cal MN治疗组对于表皮增殖的缓解作用强于Deu MN治疗组，而Deu@Cal MN治疗组棘层肥厚及表皮增生改善最佳。免疫组化与qRT-PCR结果显示，Deu@Cal组在下调IL-6、IL-17、IL-23及TNF-α等表达方面显著优于单一用药组。流式细胞术表明，Deu MN治疗组可显著抑制脾脏Th17细胞分化且降低脾脏指数，效果优于Cal MN治疗组，而Deu@Cal MN治疗组抑制作用最为明显。此外，各组小鼠体重变化平稳，心、肝、脾、肺、肾等重要器官未见组织损伤，显示该微针系统具有良好的生物安全性。

结论：本研究表明，Deu MN对于银屑病的整体治疗效果与经典外用药物Cal MN类似，Deu MN免疫调节的作用更强，Cal MN在抑制表皮增殖方面表现更优越。而Deu@Cal自锁微针贴片在银屑病治疗中同时具有良好的局部抗炎与抗增殖效果，并可有效调控系统免疫反应，表现出优于单一用药微针的协同治疗优势。其优异的疗效和安全性为银屑病等慢性炎症性皮肤病的精准治疗提供了新思路和实验依据，具有良好的临床转化潜力。

第四部分 基于皮肤转录组学的TYK2抑制剂双重释放自锁微针治疗银屑病的机制研究

背景：银屑病发病机制涉及复杂的免疫失衡与炎症信号通路异常。既往研究表明，TYK2抑制剂Deu经系统给药可以调控IL23/IL17信号通路等银屑病相关致病通路；而Deu经皮给药方式对皮损局部的免疫调控机制目前尚无研究。此外，本研究中研发的Deu@Cal MN的联合用药的治疗机理也尚无研究证明，而银屑病相关的皮肤组织转录组学研究可以为我们提供丰富的分子层面信息，对皮损组织与非皮损组织的差异表达谱分析，有助于理解疾病进展过程中的关键通路和调控网络。

目的：通过高通量转录组测序，系统评估Deu MN、Deu@Cal MN在咪喹莫特诱导的小鼠银屑病样皮损中的基因表达调控效应，解析其对各种关键基因及炎症通路、免疫细胞浸润及组织修复的综合调节机制，验证其多靶点治疗潜力。

方法：本研究对银屑病样小鼠模型组、单用Deu MN组、联合Deu@Cal MN治疗组提取背部皮损组织总RNA，经文库构建、质控及测序，获得高质量转录组数据。通过基于负二项分布的差异表达分析方法（Differential Expression analysis based on the Negative Binomial Distribution version 2，DESeq2）筛选差异表达基因（Differentially Expressed Genes，DEGs），差异表达基因的可视化分析包括火山图和Venn图。本研究还结合GO与KEGG通路富集分析、热图聚类及微环境细胞种群计数算法（Microenvironment Cell Populations-counter，MCP-counter），聚焦于重点通路和分子，从分子、通路与细胞水平系统探讨不同治疗方式对银屑病关键机制的干预效果。

结果：皮肤组织转录组学分析显示，Deu MN治疗组相较模型组共筛选出2730个上调DEGs和2432个下调DEGs，而Deu@Cal MN组在Deu MN组基础上新增301个上调和339个下调DEGs，提示二者联用具备协同调节潜力。在关键炎症信号通路方面，Deu@Cal MN组显著下调IL-17（Il17a、Il17f、Cxc11等）、IL-22（Il22、Stat3、Il22ra1等）及I型IFN（Ifnar1、Irf7、Irf8等）相关基因的表达水平，抑制程度显著优于Deu MN治疗组。我们进一步验证了Stat1、Stat3、Stat6等JAK-STAT下游转录因子的mRNA表达在Deu@Cal MN组显著降低。GO分析显示，该治疗组可显著下调免疫系统过度活化相关通路（如免疫反应介质产生、免疫球蛋白重排等），同时上调外部刺激应答、白细胞趋化与迁移、组织修复及细胞代谢调节等过程。KEGG分析结果表明，Deu@Cal MN可同时抑制IL-17、JAK-STAT、TNF等多个炎症信号通路的激活，呈现出多靶点协同干预特征。MCP-counter分析显示，与模型组相比，Deu MN、Deu@Cal MN治疗组中性粒细胞与单核细胞浸润显著减少（p＜0.01），提示其可有效缓解免疫细胞异常募集，改善皮肤炎症微环境。

结论：Deu@Cal MN可通过协同调节多条关键炎症信号通路，显著抑制局部皮损中免疫反应，降低中性粒细胞与单核细胞浸润，同时促进组织修复与免疫稳态恢复。该组合治疗策略在机制层面展现出较单药更优的抗炎与免疫调节作用，可作为银屑病精准治疗候选方案，为新型局部免疫治疗提供重要理论依据与数据支持。

ABSTRACT Part Ⅰ Pathogenic Mechanism of the TYK2 in Psoriasis and Its Potential as a Therapeutic Target Background Psoriasis is a chronic, recurrent inflammatory skin disease characterized by immune dysregulation. Its pathogenesis involves a multifactorial interplay of genetic susceptibility, environmental triggers, and immune imbalance. Among the various immunological signaling networks, the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a pivotal regulatory role. It mediates transmembrane signaling of multiple cytokines, thereby influencing the proliferation, differentiation, migration, and function of immune cells. Aberrant activation of this pathway has been closely linked to several autoimmune diseases, including psoriasis. Tyrosine kinase 2 (TYK2), a key component of the JAK family, plays a central role in the inflammatory cascade associated with psoriasis. In recent years, TYK2 inhibitors have shown promising therapeutic potential for psoriasis; however, the molecular interactions of TYK2 in local cutaneous immunity remain to be systematically explored. Objective This study aims to elucidate the mechanistic role of the TYK2 gene in the pathogenesis of psoriasis, evaluate its potential as a therapeutic target, and identify possible limitations, thereby providing a scientific basis for the development of novel therapeutic strategies. Methods This research integrates multiple transcriptomic datasets from psoriatic skin lesions, including GSE30999, GSE78097, and GSE117239. Differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), gene co-expression correlation analysis, Gene Set Enrichment Analysis (GSEA), protein-protein interaction (PPI) network analysis, and single-cell transcriptomic integration were employed to investigate the differential expression and pathogenic role of TYK2 in psoriatic lesions. Additionally, single-cell sequencing data from the GTEx project were used to characterize the expression pattern of TYK2 across various organs and cell types. Based on genome-wide association study (GWAS) results and the PrediXcan method, we inferred the tissue-specific expression levels of TYK2 in psoriasis patients and validated its cross-disease association using Summary-data-based Mendelian Randomization (SMR). Results TYK2 expression was significantly elevated in psoriatic lesions compared to non-lesional skin and was found to be co-expressed with several key psoriasis-related genes, including Interleukin-17 Receptor A (IL17RA), IFNAR2, STAT34, JAK1, IL10RB, IL4R, and MYC. TYK2 co-expressed genes were significantly enriched in the IL-17 and IL-22 signaling pathways, as well as the Type I Interferon (IFN) signaling pathway. PPI network analysis revealed that TYK2 is associated with multiple key immune signaling proteins, such as IL17RA, IFNAR12, IL10RB, STAT2, and SOCS1. These are enriched in the IL-23IL-17 axis, Th17-mediated immune responses, the JAK-STAT signaling pathway, the Type I IFN pathway, and the PI3K-Akt signaling pathway. TYK2 exhibited a pan-cellular expression pattern, including in lymphocytes. Furthermore, TYK2 expression was not limited to the skin but also notably present in organs such as the brain and liver, indicating a widespread systemic expression and potential cross-disease relevance.. Conclusion TYK2 plays a crucial role in the pathogenesis of psoriasis, participating in both immune and metabolic regulation through complex interactions with the IL-17 and IL-22 signaling pathways. Its broad tissue expression profile suggests that localized transdermal delivery of TYK2 inhibitors may reduce systemic exposure and minimize adverse effects, offering a promising approach for precision therapy in psoriasis. Keywords TYK2; Psoriasis; Therapeutic target; Transcriptomics; Single-cell analysis Part Ⅱ Fabrication and Characterization of TYK2 Inhibitor-Based Dual-Release Self-Locking Microneedle Patch Background Psoriasis is a chronic inflammatory skin disease characterized by aberrant proliferation of keratinocytes and immune dysregulation. Conventional oral therapies are often associated with systemic toxicities. Although the novel TYK2 inhibitor Deucravacitinib (Deu) has demonstrated significant clinical efficacy in psoriasis, it still poses risks of systemic adverse effects. Our preliminary findings further suggest that TYK2 exhibits a broad expression pattern across various organs and cell types in both healthy individuals and psoriasis patients. Therefore, transdermal delivery of TYK2 inhibitors may offer a promising approach to minimize systemic exposure and circumvent dosage limitations inherent in systemic administration. However, currently, there is no established transdermal delivery strategy for Deu. Calcipotriol (Cal), a vitamin D3 analogue, is a well-established topical treatment for psoriasis. Often used in combination with systemic therapies, Cal can suppress keratinocyte proliferation and promote terminal differentiation. Moreover, occlusive Cal treatment significantly reduces lesion thickness and enhances drug penetration, making it an ideal candidate for combination and comparative studies in transdermal TYK2 inhibitor delivery. Objective This study aims to develop a transdermal delivery system for the TYK2 inhibitor Deu to harness its localized therapeutic potential. Specifically, we constructed a dual-release self-locking microneedle patch (Deu@Cal MN), designed to achieve instantaneous release of Deu and sustained release of Cal. Subsequent investigations compared the therapeutic outcomes of the transdermal Deu strategy with those of traditional Cal administration. Methods A vacuum-template filling method was employed to fabricate the Deu@Cal microneedle patch. The inner ring of the microneedle tips was made from polyvinyl alcohol (PVA) to encapsulate Deu, while the outer ring and backing layer comprised methacrylated hyaluronic acid (HAMA) to deliver Cal. Upon application, the dissolvable PVA tips ensured rapid release of Deu, while the HAMA outer ring and backing layer enabled the slow, sustained release of Cal. The swelling of the HAMA ring also formed a mechanical interlocking structure, enhancing the adhesion of the microneedle patch. Comprehensive characterization was conducted, including material synthesis and analysis, swelling behavior and microstructure observation of HAMA, mechanical performance testing, drug distribution and release kinetics (via in vitro Franz diffusion and in vivo fluorescence imaging), and biocompatibility assessments (cytotoxicity and hemolysis). Results The microneedle patch exhibited excellent mechanical strength and was capable of effectively penetrating the stratum corneum for drug delivery. The HAMA outer ring showed a swelling ratio exceeding 650%, forming a stable interlocking structure, which significantly improved adhesive performance post-crosslinking. In vivo fluorescence tracking revealed that Deu was rapidly released and absorbed intradermally following insertion, while Cal maintained a stable fluorescence signal on the skin surface, confirming its capability for sustained release. Biocompatibility evaluation demonstrated negligible hemolysis and no cytotoxicity toward fibroblasts. Moreover, the micropores created by microneedle insertion healed within two hours. Conclusion This study presents an innovative transdermal delivery strategy for the TYK2 inhibitor Deu, facilitated by a dual-release self-locking microneedle patch (Deu@Cal MN). The system successfully achieves rapid intradermal delivery of Deu via the dissolvable PVA core and sustained topical release of Cal via the HAMA shell and backing layer. This localized therapeutic approach effectively targets hyperplastic psoriatic lesions while reducing the risk of systemic Deu exposure. The developed microneedle patch demonstrates favorable mechanical properties, biocompatibility, and safety, offering a novel and precise drug delivery strategy for the treatment of psoriasis and other chronic dermatological conditions. Keywords Psoriasis; TYK2 inhibitor; Calcipotriol; Microneedle; Transdermal drug delivery Part Ⅲ Therapeutic Efficacy and Safety of TYK2 Inhibitor-Based Dual-Release Self-Locking Microneedle in Psoriasiform Mouse Model Background Psoriasis is commonly associated with abnormal keratinocyte proliferation and immune dysregulation. The TYK2 inhibitor Deucravacitinib (Deu) has demonstrated promising efficacy in systemic treatment; however, prior studies have revealed that TYK2 exhibits broad expression across multiple organs and tissues, raising concerns regarding potential systemic adverse effects. Moreover, some psoriasis patients continue to exhibit persistent localized hyperplastic lesions despite oral Deu therapy, highlighting the need for optimized localized treatment strategies. Previous research has led to the development of a microneedle-based transdermal delivery system incorporating TYK2 inhibitors (Deu@Cal MN), which demonstrated favorable mechanical strength, adhesion, drug delivery efficiency, and biocompatibility. The present study aims to further evaluate the efficacy and safety of this transdermal delivery system in a murine model of psoriasis and to clarify its impact on local epidermal hyperplasia and immune regulation. Objective This study applies a Deu-based transdermal microneedle delivery system to an imiquimod (IMQ)-induced murine model of psoriasiform dermatitis. The therapeutic effects of transdermal Deu administration were compared with conventional Calcipotriol (Cal) treatment. Additionally, the efficacy and safety of the combined Deu@Cal self-locking microneedle patch were assessed, with a focus on its ability to suppress keratinocyte proliferation and modulate local and systemic immune responses. Methods BALBc mice were topically treated with IMQ cream for 8 consecutive days to induce psoriasiform lesions. From day 3, mice received local applications of different microneedle patches Control, Model (IMQ), Blank MN, Cal MN, Deu MN, and Deu@Cal MN. Disease severity was assessed by modified PASI scoring. Epidermal proliferation was evaluated via skin thickness measurements, histopathology (H&E staining), and Ki67 immunofluorescence. Inflammatory cytokines (IL-6, IL-17, IL-23, TNF-α) were quantified using qRT-PCR and immunohistochemistry. Additionally, spleen index measurements and flow cytometric analysis of Th17 cells in the spleen were conducted. Histological examination of major organs (heart, liver, spleen, lung, kidney) was performed to evaluate systemic safety. Results The Deu MN group showed therapeutic effects comparable to the Cal MN group, with improvements in erythema, scaling, and infiltration observed within five days, along with significant reductions in PASI scores. The Deu@Cal MN group exhibited the most pronounced improvement in lesion severity. Measurements of epidermal thickness (ETmin and ETmax), Ki67 positivity, and histopathological findings indicated that while Cal MN more effectively suppressed epidermal hyperplasia than Deu MN, the Deu@Cal MN patch showed the greatest reduction in acanthosis and epidermal proliferation. Immunohistochemistry and qRT-PCR data demonstrated that the Deu@Cal MN group achieved superior downregulation of IL-6, IL-17, IL-23, and TNF-α compared to monotherapy groups. Flow cytometry revealed that Deu MN treatment significantly suppressed Th17 cell differentiation and reduced the spleen index more effectively than Cal MN, with the Deu@Cal MN group exhibiting the most substantial systemic immunomodulatory effect. Furthermore, all groups maintained stable body weight, and no histological damage was observed in major organs, indicating favorable systemic biocompatibility of the microneedle platform. Conclusion This study demonstrates that Deu MN provides overall therapeutic efficacy comparable to the classical topical agent Cal MN, with stronger immunomodulatory effects, while Cal MN excels in inhibiting epidermal proliferation. Notably, the Deu@Cal self-locking microneedle patch synergistically combines anti-inflammatory and anti-proliferative effects, and effectively modulates systemic immune responses. This dual-drug microneedle system offers superior efficacy over monotherapy approaches, with excellent safety and biocompatibility. These findings provide compelling experimental evidence for a novel and precise therapeutic strategy for psoriasis and other chronic inflammatory skin diseases, highlighting its promising clinical translational potential. Keywords Psoriasis; TYK2 Inhibitor; Calcipotriol; Microneedle; Proliferation; Immune Modulation Part Ⅳ Mechanistic Insights into TYK2 Inhibitor-Based Dual-Release Self-Locking Microneedle for Psoriasis Therapy A Skin Transcriptomics-Based Study Background The pathogenesis of psoriasis involves a complex interplay of immune dysregulation and aberrant inflammatory signaling. Previous studies have demonstrated that systemic administration of the TYK2 inhibitor Deucravacitinib (Deu) effectively modulates psoriasis-related pathways, including the IL-23IL-17 axis. However, the local immunomodulatory mechanisms of transdermal Deu delivery remain unexplored. Moreover, the mechanistic basis of the combinatorial therapeutic effect of the Deu@Cal MN system developed in this study has not been elucidated. Transcriptomic profiling of psoriatic skin offers a powerful tool to investigate molecular alterations between lesional and non-lesional tissues, providing insights into critical pathways and regulatory networks underlying disease progression. Objective This study aims to systematically evaluate the gene regulatory effects of Deu MN and Deu@Cal MN treatments in an imiquimod-induced murine model of psoriasiform dermatitis using high-throughput transcriptomic sequencing. The goal is to elucidate the integrated mechanisms through which these treatments modulate key inflammatory genes, immune cell infiltration, and tissue repair, thereby verifying their potential for multi-targeted psoriasis therapy. Methods Total RNA was extracted from dorsal lesional skin of mice in the psoriasis model group, Deu MN group, and Deu@Cal MN combination therapy group. High-quality transcriptome data were obtained following library construction, quality control, and sequencing. Differentially expressed genes (DEGs) were identified using DESeq2, based on the negative binomial distribution. Visualizations included volcano plots and Venn diagrams. Functional interpretation was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, heatmap clustering, and the Microenvironment Cell Populations-counter (MCP-counter) algorithm to quantify immune cell populations. This multi-level approach explored molecular, pathway, and cellular responses to different therapeutic regimens. Results Transcriptomic analysis identified 2,730 upregulated and 2,432 downregulated DEGs in the Deu MN group relative to the model group. Notably, the Deu@Cal MN group demonstrated an additional 301 upregulated and 339 downregulated DEGs compared to the Deu MN group, suggesting enhanced synergistic regulatory potential. Inflammatory pathway analysis revealed that Deu@Cal MN significantly downregulated expression of genes in the IL-17 (e.g., Il17a, Il17f, Cxcl11), IL-22 (e.g., Il22, Stat3, Il22ra1), and type I interferon (e.g., Ifnar1, Irf7, Irf8) pathways, with stronger suppression than Deu MN monotherapy. Moreover, transcriptional levels of key JAK-STAT downstream factors such as Stat1, Stat3, and Stat6 were markedly reduced in the Deu@Cal MN group. GO analysis indicated significant downregulation of immune hyperactivation-related processes (e.g., mediator production, immunoglobulin gene rearrangement), while processes related to external stimulus response, leukocyte chemotaxis and migration, tissue repair, and metabolic regulation were upregulated. KEGG pathway enrichment further revealed that Deu@Cal MN concurrently inhibited multiple inflammatory cascades, including IL-17, JAK-STAT, and TNF pathways, highlighting a multi-targeted intervention profile. MCP-counter analysis showed a significant reduction in neutrophil and monocyte infiltration in both Deu MN and Deu@Cal MN groups (p＜0.01), indicating mitigation of abnormal immune cell recruitment and improved skin inflammatory microenvironment. Conclusion The dual-release self-locking microneedle system (Deu@Cal MNs) exerts potent immunomodulatory effects by synergistically regulating multiple key inflammatory pathways, significantly suppressing local immune responses, reducing neutrophil and monocyte infiltration, and promoting tissue repair and immune homeostasis. This combination therapy demonstrates superior anti-inflammatory and immunoregulatory efficacy compared to monotherapies and represents a promising candidate for precision treatment of psoriasis. The findings provide critical mechanistic insights and robust transcriptomic evidence supporting the development of novel localized immunotherapeutic strategies. Keywords Psoriasis; TYK2 inhibitor; Transcriptomics; Self-locking microneedles; Immune cell infiltration