皮肤疾病作为全球范围内高发的健康问题，严重影响患者的生活质量。据统计，全球约30%的人口受到各类皮肤疾病的困扰，包括银屑病、特应性皮炎、痤疮以及慢性伤口等。这些疾病不仅给患者带来瘙痒、疼痛等生理不适，还常导致患者出现心理障碍。目前，皮肤疾病的临床干预手段主要包括局部外用药物、口服药物及注射药物等。然而，现有疗法仍面临诸多挑战：传统外用制剂受限于皮肤角质层屏障，药物渗透效率低下；长期使用激素类药物易导致皮肤萎缩、毛细血管扩张等副作用；系统性口服给药则可能引发全身性不良反应，使患者依从性变差。因此，开发高效、安全、精准的皮肤递药系统，成为当前皮肤病治疗领域亟待突破的关键问题。

氧化应激在皮肤疾病中起关键作用，过量活性氧的产生会损伤细胞成分并激活炎症信号通路。尽管抗氧化剂如维生素E和白藜芦醇等具有治疗效果，但它们在临床应用中面临稳定性差和皮肤渗透性不足等问题。因此，开发新材料和递送技术来有效管理皮肤疾病中氧化应激水平十分必要。微针透皮给药技术的出现为皮肤疾病氧化应激管理提供了一种革命性方案。微针阵列通过在皮肤上形成微通道以克服传统透皮给药的屏障限制，在药物递送方面具有显著优势。本论文针对皮肤疾病氧化应激管理的临床需求和科学挑战，开发了高效的药物递送系统。研究内容包括了微针材料设计、药物负载、免疫微环境调控及评价，为皮肤病治疗提供了新思路和策略，为微针技术在皮肤病领域的应用奠定理论基础。

银屑病是一种由遗传和环境因素引起的慢性炎症性疾病，表现为皮肤上的鳞屑性斑块或红斑，全球约有1.25亿患者受其影响。氧化应激在银屑病的发展中扮演重要角色，其通过激活NLRP3炎症小体，促进细胞因子生成，导致免疫细胞稳态失调和炎症反应。目前的治疗药物，如皮质类固醇和生物制剂，因副作用强和渗透率低，不能完全满足治疗需求。因此，我们开发了一种基于补偿效应的氧化应激管理微针，用于提高药物递送效率并通过调控银屑病中氧化应激水平，抑制炎症免疫微环境，达到治疗银屑病的目的。首先，利用碱基互补配对原理合成了具有调节活性氧（ROS）水平的DNA核酸框架纳米结构（FNA）。之后针对银屑病高表达的IL-17A设计了siRNA以降低其表达水平，并利用互补链将siRNA与FNA相连形成FNA-siRNA，以解决siRNA稳定性差及细胞对siRNA摄取不足的问题。结果显示，FNA-siRNA在24 h内可实现超过80%的ROS清除效率并保持了siRNA的结构稳定性，同时有超49%的siRNA被细胞摄取，增强了siRNA对IL-17A表达的抑制作用。进一步，FNA-siRNA通过调控ROS水平，降低了细胞焦亡水平，促进了巨噬细胞向M2型极化，提高了动物脾脏中调节性T细胞（Tregs）数量，抑制了炎性免疫微环境。此外，使用微针递送FNA-siRNA使药物在皮下400 µm处仍具有较高浓度，并且延长了药物在皮肤中的滞留时间，实现了药物的深层递送，提高了药物治疗效率。最终使银屑病面积与严重程度指数（PASI）总分在2分以下，银屑病症状完全缓解，为银屑病的氧化应激管理免疫治疗提供了新的思路和方法。

皮肤伤口感染是临床上常见的疾病，严重的可导致败血症和器官衰竭，每年造成医疗费用高达750亿美元。氧化应激水平管理对伤口愈合至关重要。在伤口初期，促进ROS生成可以杀菌；而在伤口后期，抑制炎症免疫环境可以促进伤口愈合。但常规敷料功能单一，难以满足伤口愈合各阶段需求。此外，生物膜和抗生素耐药性问题也不容忽视。因此，开发一种能够有效递送药物、调控氧化应激水平和免疫微环境的给药系统非常重要。针对这一临床难题，本研究开发了一种具有核壳结构的微针，用于对感染性伤口的协同治疗，实现在早期抗菌、后期抑制炎症免疫微环境促进伤口愈合的治疗效果。首先，利用水合还原法以明胶为分散剂制备了粒径均一、性能稳定，具有过氧化物酶（POD）活性的铜纳米酶。然后，将明胶-铜溶液离心干燥后制备出微针外层，同时利用苯硼酸修饰的透明质酸（HAPBA）与聚乙烯醇（PVA）构建ROS响应性水凝胶作为内层载体，负载具有免疫调节作用的白细胞介素4（IL-4），最终形成具有核壳结构的微针。该系统在体内外实验中展现出显著的治疗优势：接触伤口后，外层明胶穿破生物膜快速溶解，释放的铜纳米酶通过催化伤口处过氧化氢（H₂O₂）产生ROS，对细菌实现完全杀灭；在炎症微环境持续存在下，内层HAPBA-PVA水凝胶响应ROS控释IL-4促使巨噬细胞向M2型极化，抑制伤口区域炎症，最终使感染性伤口区域降低至10%。进一步的转录组测序结果显示，微针治疗组通过促进细胞迁移基因（Wnt、Myb、Tcf3等）及抑制促炎基因（Smad3、Tnf、Ptgs2等）的表达，促进了伤口的愈合。这种通过基于伤口微环境特征进行ROS及免疫调控的给药策略，为突破现有感染性伤口治疗瓶颈提供了新的解决方案。

综上所述，本研究主要通过调控皮肤疾病的氧化应激水平及炎性免疫微环境，并利用微针技术独特的原位药物递送机制及其显著增强药物深层渗透的能力，成功实现了对银屑病及感染性伤口的治疗。

Skin diseases, as prevalent global health issues, significantly impair patients' quality of life. Statistics indicate that approximately 30% of the global population suffers from various dermatological conditions, including psoriasis, atopic dermatitis, acne, and chronic wounds. These diseases not only cause physiological discomfort such as itching and pain but also often lead to psychological distress. Current clinical interventions primarily include topical, oral, and injectable medications. However, current existing therapies face multiple challenges: traditional topical formulations are limited by the stratum corneum barrier and result in poor drug penetration; prolonged use of corticosteroids may cause side effects such as skin atrophy and telangiectasia; systemic oral administration can trigger adverse systemic reactions and reduce patient compliance. Therefore, developing efficient, safe, and precise drug delivery systems has become a critical challenge in dermatological treatment.

Oxidative stress plays a pivotal role in skin diseases, in which excessive reactive oxygen species (ROS) damage cellular components and activate inflammatory pathways. Although antioxidants such as vitamin E and resveratrol exhibit therapeutic potential, their clinical application is hindered by poor stability and inadequate skin penetration. Thus, novel materials and delivery technologies are urgently needed to effectively manage oxidative stress in skin diseases. Microneedle-based transdermal drug delivery offers a revolutionary solution by creating microchannels in the skin to overcome barrier limitations. This thesis addresses the clinical and scientific challenges of oxidative stress management in skin diseases by developing advanced drug delivery systems, focusing on microneedle material design, drug loading, immune microenvironment modulation, and evaluation, thereby providing new strategies and tools for dermatological therapy.

Psoriasis is a chronic inflammatory disease influenced by genetic and environmental factors, characterized by scaly plaques or erythema, affecting approximately 125 million patients worldwide. Oxidative stress significantly contributes to psoriasis progression by activating the NLRP3 inflammasome, promoting cytokine production, and disrupting immune cell homeostasis. Current treatments, such as corticosteroids and biologics, fail to fully meet clinical needs due to side effects and low penetration. To address this, we developed a microneedle system based on a compensatory oxidative stress management strategy to enhance drug delivery efficiency and modulate the inflammatory immune microenvironment. First, a DNA framework nucleic acid (FNA) nanostructure was synthesized via base-pairing principles to regulate ROS levels. Subsequently, siRNA targeting psoriasis-associated IL-17A was designed and conjugated to FNA (FNA-siRNA) to improve siRNA stability and cellular uptake. The results demonstrated that FNA-siRNA achieved over 80% ROS scavenging within 24 h while maintaining siRNA stability, realized more than 49% siRNA phagocytosed by cells, and significantly suppressed IL-17A expression. Furthermore, FNA-siRNA reduced pyroptosis, promoted M2 macrophage polarization, and increased regulatory T cells (Tregs) populations in the spleen, thus mitigating inflammation degree. Our microneedle delivery system enabled deep drug penetration (400 µm) and prolonged skin retention, achieving complete psoriasis remission (PASI score <2) and offering a novel oxidative stress-based immunotherapeutic approach.

Skin wound infections, a common clinical condition, can lead to severe sepsis and organ failure, incurring annual healthcare costs of up to $75 billion. Oxidative stress management is crucial for wound healing: early-stage ROS generation aids bacterial killing, while later-stage inflammation suppression promotes tissue repair. Conventional dressings lack multifunctionality and fail to address biofilm formation and antibiotic resistance. To overcome these shortcomings, we developed a core-shell microneedle system for synergistic treatment, enabling early-stage antibacterial action and late-stage immunomodulation. Copper nanozymes with peroxidase (POD)-like activity were synthesized using gelatin as a dispersant and formed the microneedle outer layer. A ROS-responsive hydrogel core (HAPBA-PVA) loaded with interleukin-4 (IL-4) was designed for controlled immunomodulation. In vitro and in vivo studies demonstrated that the gelatin underwent rapid dissolution upon application, triggering the release of copper nanozymes to catalyze endogenous H₂O₂ to eradicate bacteria. Sustained release of IL-4 under inflammatory conditions promoted M2 macrophage polarization, reducing wound inflammation to 10%. Transcriptomic analysis revealed upregulated cell migration genes (Wnt, Myb, Tcf3) and downregulated pro-inflammatory genes (Smad3, Tnf, Ptgs2), thus accelerating skin wound healing. This microenvironment-responsive strategy provides a breakthrough in infected wound treatment.

In summary, this study successfully treated psoriasis and infected wounds by modulating oxidative stress and inflammatory immune microenvironments, leveraging microneedle technology for targeted drug delivery and enhanced skin penetration. The findings establish a theoretical foundation for microneedle applications in dermatology.