Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission

• DOI: 10.1186/s12951-024-02517-1
• Publication Date: 2024-05-24T20:20:54Z
• Authors: Zhidi Lin; Guangyu Xu; Xiao Lu; Siyang Liu; Fei Zou; Xiaosheng Ma; Jianyuan Jiang; Hongli Wang; Jian Song
• Keywords: Internalization; Exosome

Abstract Background Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead apoptosis during CEP IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis Despite their major success in drug delivery, full potential exosomes remains untapped. Materials methods In vitro vivo models were established using lipopolysaccharide (LPS). We designed genetically engineered (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on surface carrying antioxidant transcription factor nuclear E2-related 2 (Nrf2). The affinity between CAP-Nrf2-Exos was evaluated internalization assays imaging assays. qRT‒PCR, Western blotting immunofluorescence performed examine expression level Nrf2 subcellular localization Drp1. Mitochondrial function measured JC-1 probe MitoSOX Red. morphology visualized MitoTracker staining transmission electron microscopy (TEM). After subendplate injection exosomes, degree IVDD validated radiologically histologically. Results found cargo delivery efficiency after packaging increased modification. facilitated chondrocyte-targeted activated endogenous defence system cells. inhibited Drp1 S616 phosphorylation translocation, thereby preventing fragmentation dysfunction. LPS-induced cell alleviated CAP-Nrf2-Exo treatment. a rat model successfully attenuated exhibited better repair capacity than natural exosomes. Conclusion Collectively, our findings showed exosome-mediated effective strategy treating degeneration. Graphic abstract delivered into cells inhibiting Drp1-mediated