Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.

Abstract

Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering <b>mito</b>chondria mediated by <b>m</b>itophagy-<b>e</b>nhanced <b>n</b>anoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin <i>mRNA</i>, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.