Profibrogenic macrophage-targeted delivery of mitochondrial protector via exosome formula for alleviating pulmonary fibrosis

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 (Mø^mitohigh) and fibrosis. Among the Mø^mitohigh 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 "exosome^MMP19 (Exo^MMP19)", 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 (Exo^Tx)", was engineered to display D-mannose on the surface while encapsulating siDrp1 inside. Prior delivery of Exo^MMP19 degraded excessive ECM and thus paved the way for Exo^Tx to be delivered into Mø^mitohigh, where Exo^Tx inhibited mitochondrial fission and alleviated PF. This study has not only identified Mø^mitohigh as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.