Asthma impacts over 300 million patients globally, with significant health implications, especially in cases of its allergic subtype. The disease is characterized by a complex interplay of airway inflammation and immune responses, often mediated by Th cell-related cytokines. In this study, we engineered lipid nanoparticles (LNPs) to specifically deliver therapeutic siRNA via the transferrin receptor to T cells. Strain-promoted azide-alkyne cycloaddition (SPAAC) was employed for the conjugation of transferrin ligands to PEGylated lipids in the LNPs, with the goal of enhancing cellular uptake and gene knockdown. The obtained LNPs exhibited characteristics that make them suitable for pulmonary delivery. Using methods such as nanoparticle tracking analysis (NTA) and enzyme-linked immunosorbent assay (ELISA), we determined the average number of transferrin molecules bound to individual LNPs. Additionally, we found that cellular uptake was ligand-dependent, achieving a GATA3 knockdown of more than 50% in relevant and models. Notably, our findings highlight the limitations inherent to modifying the surface of LNPs, particularly with regard to their targeting capabilities. This work paves the way for future research aimed at optimizing targeted LNPs for the treatment of immunologic diseases such as allergic asthma.

中文翻译：

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定制脂质纳米粒子用于过敏性哮喘中的 T 细胞靶向：深入了解功效和特异性

哮喘影响全球超过 3 亿患者，对健康产生重大影响，尤其是过敏亚型的情况。该疾病的特点是气道炎症和免疫反应之间复杂的相互作用，通常由 Th 细胞相关细胞因子介导。在这项研究中，我们设计了脂质纳米颗粒 (LNP)，通过转铁蛋白受体将治疗性 siRNA 特异性递送至 T 细胞。采用应变促进的叠氮-炔环加成 (SPAAC) 将转铁蛋白配体与 LNP 中的聚乙二醇化脂质缀合，目的是增强细胞摄取和基因敲低。获得的 LNP 表现出适合肺部递送的特性。使用纳米颗粒追踪分析 (NTA) 和酶联免疫吸附测定 (ELISA) 等方法，我们确定了与单个 LNP 结合的转铁蛋白分子的平均数量。此外，我们发现细胞摄取是配体依赖性的，在相关模型中实现了超过 50% 的 GATA3 敲低。值得注意的是，我们的研究结果强调了修饰 LNP 表面所固有的局限性，特别是在其靶向能力方面。这项工作为未来旨在优化靶向 LNP 以治疗过敏性哮喘等免疫性疾病的研究铺平了道路。