Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles.

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.