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Thorax, Dec 04 2024, thorax-2024-221793 | https://doi.org/10.1136/thorax-2024-221793
Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles
Miji Kim,1,2,3 Sujeong Park,1,3,4 Nayoung Lee,1 Dohyun Kim,1 Dongwoo Kim,1 Yang Jin,5 Seon-Jin Lee,3,4 Jung Joo Hong,2,3 Heedoo Lee1
1Department of Biology and Chemistry, Changwon National University, Changwon, South Korea
2Korea Research Institute of Bioscience and Biotechnology National Primate Research Center, Ochang, South Korea
3University of Science and Technology, Daejeon, South Korea
4Environmental Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, South Korea
5Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Correspondence to Professor Heedoo Lee
S-JL, JJH and HL contributed equally.
1Department of Biology and Chemistry, Changwon National University, Changwon, South Korea
2Korea Research Institute of Bioscience and Biotechnology National Primate Research Center, Ochang, South Korea
3University of Science and Technology, Daejeon, South Korea
4Environmental Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, South Korea
5Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Correspondence to Professor Heedoo Lee
S-JL, JJH and HL contributed equally.
Abstract
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.
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.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-06)
- 국내 연구진
- 생명과학 > 생리학
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