RNA medicines have become a promising platform for therapeutic use in recent years. Understanding the immunomodulatory effects of novel mRNA-lipid nanoparticles (LNPs) is crucial for future therapeutic development. An in vitro whole blood assay was developed to assess the impact of mRNA-LNPs on immune cell function, cytokine release, and complement activation. mRNA-LNPs significantly increased CD69 expression on T cells and natural killer cells, and CD80/CD86 on myeloid subsets, in a dose-dependent fashion. Furthermore, mRNA-LNPs elicited a robust release of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, monocyte chemoattractant protein-1, IL-6, and IP-10, indicating a potent immune response. Notably, mRNA-LNPs stimulate early cytokine production prior to triggering immune cell activation, suggesting a temporal and biological relationship. Moreover, mRNA-LNPs induce complement activation via the alternative pathway, as evidenced by increased serum sC5b-9, C3a, and Bb, which can amplify the inflammatory response and potentially impact safety. In vitro effects of mRNA-LNPs in whole blood of healthy human donors were compared with those from disease cohorts including systemic lupus erythematosus, type 2 diabetes mellitus, and cancer donors. The differences in mRNA-LNP effects on samples from healthy and diseased populations may impact therapeutic efficacy or toxicity, indicating a need for tailoring LNPs for specific target populations.

中文翻译：

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mRNA-LNP 在不同健康状况下在人全血检测中诱导免疫激活和细胞因子释放


近年来，RNA 药物已成为一个有前途的治疗应用平台。了解新型 mRNA-脂质纳米颗粒 （LNP） 的免疫调节作用对于未来的治疗开发至关重要。开发了一种体外 全血测定法来评估 mRNA-LNPs 对免疫细胞功能、细胞因子释放和补体激活的影响。mRNA-LNPs 以剂量依赖性方式显着增加 T 细胞和自然杀伤细胞上的 CD69 表达，以及髓系亚群上的 CD80/CD86 表达。此外，mRNA-LNPs 引发了促炎细胞因子的强烈释放，包括肿瘤坏死因子-α、白细胞介素 （IL）-1β、单核细胞趋化蛋白-1、IL-6 和 IP-10，表明有效的免疫反应。值得注意的是，mRNA-LNPs 在触发免疫细胞活化之前刺激早期细胞因子的产生，这表明存在时间和生物学关系。此外，mRNA-LNPs 通过替代途径诱导补体激活，血清 sC5b-9、C3a 和 Bb 增加证明了这一点，这会放大炎症反应并可能影响安全性。 将健康人类供体全血中 mRNA-LNPs 的体外效应与系统性红斑狼疮、2 型糖尿病和癌症供体等疾病队列的体外效应进行了比较。mRNA-LNP 对健康人群和患病人群样本影响的差异可能会影响治疗效果或毒性，表明需要为特定目标人群定制 LNP。