Fig. 1. Schematic illustration showing the strategy of using a joint-engineered mesenchymal stem cell (Pg-Fe-hMSC) to enable a powerful and sustained intercellular mitochondrial delivery specialized to injured lung epithelial cells (LECs) for the potent intervention of pulmonary fibrosis (PF).

These joint-engineered hMSC using iron oxide nanoparticles (IONPs) and pioglitazone realized powerful intercellular mitochondrial transfer, which is mainly due to the promoted mitochondrial biogenesis through the PGC-1α pathway and augmented mitochondrial transfer through the gap junction facilitated trafficking (e.g. annular gap junction mediated internalization). The Pg-Fe-hMSC can be used as both a mitochondrial generation factory and a smart vehicle for selective mitochondrial transfer to injured lung cells, showing the advantages of enabling efficient and sustained mitochondrial transfer. Consequently, Pg-Fe-hMSC achieves efficient intervention treatment for PF. This demonstrated strategy provides a potential approach to prepare mitochondria donor cells and mitochondria vehicles for workable mitochondrial replenishment treatments. Cx43 connexin 43, NRF1 nuclear respiratory factor 1, TFAM mitochondrial transcription factor A, JNK c-Jun N-terminal kinase, TCA tricarboxylic acid cycle, ROS reactive oxygen species, TGF-β transforming growth factor-β. Figure was partially created with BioRender.com.