Mitochondria-enriched nanovesicles: A novel approach for treating radiation-induced skin injury.

Radiation-induced skin injury (RSI) is characterized by persistent mitochondrial dysfunction and compromised DNA repair mechanisms, posing significant challenges for clinical management. To address this, we engineered mitochondria-enriched nanovesicles (NVs) derived from human umbilical cord mesenchymal stem cells (hUMSCs), designed to deliver bioactive mitochondrial components to irradiated skin tissues. Using established in vitro and in vivo models of X-ray-induced RSI, we demonstrated efficient NV internalization into epidermal and dermal cells, leading to restoration of mitochondrial ultrastructure and metabolic function, attenuation of reactive oxygen species (ROS), and facilitation of DNA damage repair. Data-independent acquisition (DIA) proteomic profiling further indicated that NVs significantly upregulated key DNA repair proteins (including POLD3, POLE4, RFC1, and ERCC6), which were downregulated after irradiation, and activated the PINK1-Parkin mitophagy pathway. Additionally, NVs restored mitochondrial dynamics by suppressing DRP1-mediated fission and enhancing MFN1/2-dependent fusion, collectively promoting cellular homeostasis. These findings support the development of a cell-free, mitochondria-based nanotherapeutic strategy that concurrently targets DNA repair and mitochondrial quality control, presenting a scalable and promising treatment for RSI and potentially other radiation-induced disorders.