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 mitochondria mediated by mitophagy-enhanced nanoparticle (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 mRNA, 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.

中文翻译：

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线粒体自噬增强纳米颗粒工程线粒体恢复线粒体库稳态以缓解肺纤维化


肺纤维化 （PF） 是一种间质性肺病，与线粒体池稳态的破坏密切相关，线粒体池稳态是一种受肺细胞内功能性和功能失调的线粒体影响的微妙平衡。线粒体转移是一种新兴技术，通过外源性线粒体递送增加功能性线粒体;然而，在 PF 过程中，由于线粒体自噬受损，功能失调的线粒体的持续存在阻碍了对线粒体转移的治疗效果。在此，我们报道了由 mitophagy-e nhanced nanoparticle （Mito-MEN） 介导的工程化线粒体软骨，它促进了治疗 PF 的功能和功能失调线粒体的同步调节。线粒体自噬增强纳米颗粒 （MEN） 是通过 Parkin mRNA 的封装制造的，静电相互作用有利于 MON 锚定分离的健康线粒体以构建 Mito-MEN。Mito-MEN 通过提高线粒体递送效率增加功能性外源性线粒体的负荷，并促进功能失调的内源性线粒体的线粒体自噬。在博来霉素 （BLM） 诱导的 PF 小鼠模型中，Mito-MEN 修复线粒体功能并有效缓解 PF 相关表型。本研究为线粒体池稳态的同步调整提供了有力的工具，并为泛线粒体疾病治疗提供了转化方法。