南京中医药大学曹鹏教授团队揭示紫苏叶来源的胞外囊泡样颗粒跨界递送miRNA治疗银屑病的机制

近期，南京中医药大学曹鹏教授团队对植物来源的细胞外囊泡在炎症性皮肤病治疗潜力进行了深入研究，提出了利用紫苏叶来源的细胞外囊泡样颗粒（PLEVPs）治疗银屑病的新策略，并建立了涵盖药用植物筛选、分子谱分析、机制研究和体内验证的全面研究框架。研究发现，PLEVPs通过递送功能性miRNA pab-miR396a-5p，精准调控IL-17信号通路，有效缓解银屑病症状，从而减轻炎症和角质形成细胞过度增殖，展现出强大的局部治疗和临床转化潜力。该研究成果以“紫苏叶衍生的细胞外囊泡样颗粒携带Pab-miR-396a-5p通过调节IL-17信号传导缓解牛皮癣”为题在线发表于国际期刊《研究》。

　　

背景

银屑病是一种常见的慢性炎症性皮肤病，其特征是复发性红斑，涉及角质形成细胞异常增生和免疫失调，严重影响患者的生活质量。尽管目前的治疗方法——例如皮质类固醇、免疫抑制剂和靶向IL-17的生物制剂——可以缓解症状，但它们通常伴有明显的副作用、高昂的成本以及对长期安全性的担忧。与此同时，传统中医药 (TCM) 具有多靶点调控优势，但其起效缓慢且机制不明，限制了其在临床上的广泛应用。

近年来，细胞外囊泡 (EV) 因其天然的纳米级结构、优异的生物相容性和信号传导能力，已成为极具前景的生物运载载体。与哺乳动物来源的 EV 相比，植物来源的细胞外囊泡样颗粒 (EVP) 具有诸多优势，包括低免疫原性、高产量和广泛应用。它们在抗炎、抗氧化和免疫调节应用方面已展现出治疗潜力。值得注意的是，植物 EVP 天然富含功能性微小RNA (miRNA)，这些miRNA可以调节跨界炎症反应，这为开发基于自然的治疗策略提供了突破性机遇。

研究进展

南京中医药大学曹鹏教授团队系统探索了植物来源的细胞外囊泡（EVs）在炎症性皮肤病中的治疗潜力，并提出了利用紫苏叶来源的细胞外囊泡样颗粒（PLEVPs）治疗银屑病的新策略。该研究建立了涵盖药用植物筛选、成分和功能分析、机制研究以及体内评价的综合框架。

研究团队首先从十种常用药用植物中分离EVP，并根据其在IL-6诱导的HaCaT角质形成细胞炎症模型中的作用进行初步筛选。在候选EVP中，PLEVP通过有效减少活性氧（ROS）积累和下调促炎细胞因子（如IL-6和IL-1β）表现出最强的抗氧化和抗炎活性。为了探究这些作用的机制，研究人员对PLEVP的RNA、蛋白质、脂质和代谢物组成进行了全面分析。与粗紫苏叶提取物相比，PLEVP富含神经酰胺、鞘脂、黄酮类化合物和其他调节炎症的次级代谢产物。它们的RNA谱显示小RNA含量丰富，蛋白质含量集中在低分子量范围内（图1）。这些结构特征共同巩固了PLEVP在分子水平上的治疗潜力。

为了强调外用制剂在银屑病治疗中的重要性，研究人员将PLEVPs整合到水凝胶递送系统中。体内研究表明，该水凝胶显著增强了PLEVPs的皮肤粘附性，延长了其滞留时间，并改善了PLEVPs的透皮渗透性，同时还稳定了囊泡结构。该制剂为局部、持续和靶向递送提供了一个强大的平台。

在咪喹喹莫特 (IMQ) 诱发的银屑病样小鼠模型中，PLEVP 水凝胶显著缓解了典型的银屑病症状，包括红斑、脱屑和表皮增厚。组织学分析显示角质形成细胞增殖减少，炎症细胞浸润减少。流式细胞术和 ELISA 进一步证实，PLEVP 治疗抑制了 Th17 相关细胞因子（IL-17a、IL-23 和 IL-6）的表达，从而有助于恢复免疫稳态（图 2）。

为了阐明潜在的分子机制，研究团队进行了RNA测序（RNA-seq）分析。结果显示，PLEVP广泛下调了与银屑病进展密切相关的炎症相关基因，并在IL-17、NF-κB和JAK-STAT等经典炎症信号通路中显著富集。这些发现通过qPCR进一步验证，为PLEVP治疗作用的机制基础提供了强有力的证据。

To further identify the key active component responsible for PLEVPs' anti-psoriatic function, the team conducted small RNA sequencing on keratinocytes treated with PLEVPs (Figure 3). The analysis revealed a specific miRNA—pab-miR396a-5p—that was highly enriched in PLEVPs and successfully delivered into recipient cells, where its expression was significantly upregulated. Bioinformatic predictions indicated that this miRNA targets HSP90, a heat shock protein known to function as a key molecular chaperone for the IL-17 receptor complex and a central player in psoriasis-related inflammatory signaling. These findings suggest that pab-miR396a-5p is likely the core functional mediator of the immunomodulatory effects exerted by PLEVPs.

In functional validation experiments, transfection of pab-miR396a-5p mimics led to a significant downregulation of HSP90 and IL-17 pathway–associated molecules, including Il17ra, Il17rc, Il17rd, phosphorylated p65, and phosphorylated STAT3, while also suppressing the secretion of multiple pro-inflammatory cytokines. Furthermore, miRNA inhibition experiments demonstrated that blocking pab-miR396a-5p markedly weakened the anti-inflammatory effects of PLEVPs, confirming its role as a key functional mediator.

To assess its standalone therapeutic potential, the research team developed a lipid nanoparticle (LNP) delivery system encapsulating pab-miR396a-5p and evaluated its efficacy in an IMQ-induced psoriasis-like mouse model. The results showed that the LNP@miRNA group effectively improved psoriatic lesions, reduced inflammatory cytokine levels, and significantly alleviated PASI scores, skin thickness, and histological inflammation. The therapeutic efficacy was comparable to that of PLEVPs and even surpassed the clinically used tacrolimus, further validating the in vivo effectiveness and translational potential of this miRNA-based therapy.

Finally, Figure 5 illustrates the overall mechanism proposed in this study: PLEVPs deliver miRNA pab-miR396a-5p → target HSP90 → inhibit the JAK/STAT and NF-κB pathways → downregulate IL-17 signaling → alleviate psoriatic inflammation and keratinocyte hyperproliferation.

Outlook
This study is the first to systematically demonstrate that Perilla leaf–derived extracellular vesicle-like particles (PLEVPs) can deliver miRNA pab-miR396a-5p to precisely modulate the IL-17 signaling pathway, thereby significantly alleviating psoriatic inflammation. These findings offer a novel therapeutic strategy for the application of plant-derived extracellular vesicles in treating inflammatory skin diseases. As a natural, safe, and highly biocompatible delivery vehicle, PLEVPs show strong potential for topical therapy and represent a valuable step toward the modernization and precision delivery of active components in traditional Chinese medicine. Moreover, this work lays the foundation for developing miRNA-based phytotherapeutics.