Airway administered artificial mitochondria-enriched nanovesicles for efficient and selective mitochondria transfer to intervene in pulmonary fibrosis

Mitochondrial transplantation is a promising therapeutic approach involving the transfer of exogenous mitochondria into diseased cells to restore impaired mitochondrial homeostasis. However, its clinical translation is severely limited by the lack of efficient methods for precise and potent mitochondria transfer. Inspired by natural mitochondria-containing vesicles, we develop mesenchymal stem cell-derived biomimetic nanovesicles with high mitochondrial loading capacity and augmented extracellular mitochondrial stability. These nanovesicles exhibit an ability to efficiently and selectively deliver mitochondrial cargo to injured cells, which is potentially ascribed to the specific interaction between very late antigen-5 on the nanovesicle surface and pathologically upregulated fibronectin on injured cells. In a mouse pulmonary fibrosis model, these nanovesicles successfully deliver healthy mitochondria to injured lung epithelial cells through airway administration, resulting in a significant reduction in fibrotic progression. This study introduces a design of mitochondria-enriched biomimetic nanovesicles for effective and targeted mitochondria transfer, offering a nanotechnology-based strategy to advance mitochondrial transplantation therapy. Zhang and colleagues develop mesenchymal stem cell-derived artificial nanovesicles encapsulating bioactive mitochondria, enabling targeted mitochondria delivery to injured lung cells via airway administration to effectively intervene in pulmonary fibrosis.