Profibrogenic macrophage-targeted delivery of mitochondrial protector via exosome formula for alleviating pulmonary
Wei Zhang1, Zhuo Wan2, Di Qu3,4
1Department of Pulmonary and Critical Care Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.
Abstract:
Pulmonary fibrosis (PF) is a devastating lung disease with limited treatment options. During this pathological process, the profibrogenic macrophage subpopulation plays a crucial role, making the characterization of this subpopulation fundamentally important. The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass (Mømitohigh) and fibrosis. Among the Mømitohigh subpopulation of CD206+ M2, characterized by higher expression of dynamin 1-like (Drp1), as determined by flow cytometry and RNA-seq analysis, a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics. A pathfinder exosome called "exosomeMMP19 (ExoMMP19)", was constructed to display matrix metalloproteinase-19 (MMP19) on the surface to locally break down the excessive extracellular matrix (ECM) in the fibrotic lung. A therapeutic exosome called "exosome therapeutics (ExoTx)", was engineered to display D-mannose on the surface while encapsulating siDrp1 inside. Prior delivery of ExoMMP19 degraded excessive ECM and thus paved the way for ExoTx to be delivered into Mømitohigh, where ExoTx inhibited mitochondrial fission and alleviated PF. This study has not only identified Mømitohigh as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.
Insights
Researchers identified profibrotic macrophages with high mitochondrial mass (Mømitohigh) linked to pulmonary fibrosis (PF). A novel exosome therapy, combining ECM degradation and mitochondrial fission inhibition, successfully reversed PF in a preclinical model.
Area of Science:
- Biomedical research
- Cell biology
- Pulmonary medicine
Background:
- Pulmonary fibrosis (PF) is a severe lung disease with few treatments.
- Profibrogenic macrophages are key players in PF development.
- Characterizing these macrophages is crucial for therapeutic development.
Purpose of the Study:
- To identify and characterize profibrogenic macrophages in PF.
- To develop and test a novel exosome-based therapeutic strategy for PF.
Main Methods:
- Flow cytometry and RNA-seq to identify Mømitohigh macrophages.
- Engineered exosomes (ExoMMP19 and ExoTx) for targeted delivery.
- Preclinical evaluation of the combined exosome therapy.
Main Results:
- Mømitohigh macrophages, expressing high levels of dynamin 1-like (Drp1), correlate with lung fibrosis.
- ExoMMP19 degraded extracellular matrix (ECM), facilitating ExoTx delivery.
- ExoTx inhibited mitochondrial fission and alleviated PF.
Conclusions:
- Mømitohigh macrophages are identified as a profibrotic cell population.
- A dual-exosome strategy effectively reverses pulmonary fibrosis.
- This approach offers a promising therapeutic avenue for PF treatment.
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