Introduction Alveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular vesicles (EVs) have emerged as a promising drug delivery platform due to their minimal cytotoxicity. However, precise targeting of specific cell types and the rapid lysosomal degradation of EVs within recipient cells remain persistent challenges. Method In this study, we explored the biological significance of SP-A-EVs as novel drug delivery systems for combating lung inflammation. We first verified that respiratory EVs express SP-A receptor (SP-R210), facilitating the conjugation of SP-A with EVs. The delivery efficiency, cellular internalisation pathways and therapeutic effects were evaluated using an in vivo mouse model. Results SP-A-EVs were robustly internalised into AMs both in vitro and in vivo. Furthermore, our investigation revealed that the toll-like receptor 4-mediated endocytosis pathway was employed for the uptake of SP-A-EVs, significantly delaying their degradation compared with natural EVs, which primarily followed the conventional lysosomal degradation pathway within AMs. In a functional study, we successfully loaded anti-inflammatory microRNA ( let-7b ) into SP-A-EVs, leading to the suppression of AM activation and the alleviation of lung inflammation induced by lipopolysaccharide. Conclusion These findings underscore the potential of SP-A-EVs as highly effective drug delivery systems for targeted therapeutics in lung-related disorders, capitalising on the strong affinity between AMs and SP-A and the modulation of cellular internalisation. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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用于肺部炎症治疗的高级 MicroRNA 递送：表面活性剂蛋白 A 控制细胞内化和细胞外囊泡降解


简介 肺泡巨噬细胞 （AM） 是抵御病原体的第一道防线，这些病原体会在肺部引发炎症反应，并对表面活性剂蛋白 A （SP-A） 表现出很强的亲和力。细胞外囊泡 （EV） 由于其最小的细胞毒性而成为一种很有前途的药物递送平台。然而，精确靶向特定细胞类型和受体细胞内 EV 的快速溶酶体降解仍然是持续的挑战。方法 在本研究中，我们探讨了 SP-A-EVs 作为对抗肺部炎症的新型药物递送系统的生物学意义。我们首先验证了呼吸 EV 表达 SP-A 受体 （SP-R210），促进 SP-A 与 EV 的结合。使用体内小鼠模型评估递送效率、细胞内化途径和治疗效果。结果 SP-A-EVs 在体外和体内均被稳健地内化到 AM 中。此外，我们的调查显示，toll 样受体 4 介导的内吞途径用于 SP-A-EVs 的摄取，与天然 EVs 相比，显着延迟了它们的降解，天然 EV 主要遵循 AM 内的常规溶酶体降解途径。在一项功能研究中，我们成功地将抗炎 microRNA （let-7b） 加载到 SP-A-EVs 中，从而抑制 AM 激活并减轻脂多糖诱导的肺部炎症。结论这些发现强调了 SP-A-EVs 作为肺相关疾病靶向治疗的高效药物递送系统的潜力，利用 AM 和 SP-A 之间的强亲和力以及细胞内化的调节。与研究相关的所有数据都包含在文章中或作为补充信息上传。