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.