Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria

Mitochondria-targeted therapies hold great promise for treating metabolic syndrome, neurodegeneration, and cancers associated with mitochondrial dysfunction or genetic mutations. However, its advancement is significantly limited by the lack of effective and biocompatible targeted delivery systems. Here, we introduce mitofusin-decorated extracellular vesicles (MFNEVs) as a natural-sourced nanoplatform for efficient mitochondrial delivery of various cytoplasm-sensitive macromolecular cargos. The surface-displayed mitofusin proteins MFN1 and MFN2 direct MFNEVs to localize to mitochondria, as confirmed by confocal imaging and gel electrophoresis analysis. In both in vitro and in vivo models, siRNA-loaded MFNEVs effectively reduce the expression of mitochondrial DNA-encoded genes. Moreover, sgRNA-loaded MFNEVs can achieve CRISPR-based mitochondrial gene editing, resulting in a decreased mitochondrial DNA content. Mechanistic studies further reveal that the delivery is facilitated by the cooperation of the mitochondrial fusion machinery. These findings establish the feasibility and versatility of MFNEVs as a promising delivery solution for mitochondrial therapeutics.