This study investigates the potential of chondrocyte-targeted exosome-mediated delivery of nuclear factor E2-related factor 2 (Nrf2) to alleviate cartilaginous endplate (CEP) degeneration, a key contributor to intervertebral disc degeneration (IVDD). The researchers designed genetically engineered exosomes (CAP-Nrf2-Exos) that express chondrocyte-affinity peptide (CAP) and carry the antioxidant transcription factor Nrf2. In vitro and in vivo models of CEP degeneration were established using lipopolysaccharide (LPS). The results showed that CAP-Nrf2-Exos efficiently delivered Nrf2 to CEP cells, activated the endogenous antioxidant defense system, inhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, and prevented mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was significantly reduced by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, CAP-Nrf2-Exos successfully attenuated CEP degeneration and IVDD, demonstrating better repair capacity compared to natural exosomes. The findings suggest that chondrocyte-targeted exosome-mediated delivery of Nrf2 is an effective strategy for treating CEP degeneration.This study investigates the potential of chondrocyte-targeted exosome-mediated delivery of nuclear factor E2-related factor 2 (Nrf2) to alleviate cartilaginous endplate (CEP) degeneration, a key contributor to intervertebral disc degeneration (IVDD). The researchers designed genetically engineered exosomes (CAP-Nrf2-Exos) that express chondrocyte-affinity peptide (CAP) and carry the antioxidant transcription factor Nrf2. In vitro and in vivo models of CEP degeneration were established using lipopolysaccharide (LPS). The results showed that CAP-Nrf2-Exos efficiently delivered Nrf2 to CEP cells, activated the endogenous antioxidant defense system, inhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, and prevented mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was significantly reduced by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, CAP-Nrf2-Exos successfully attenuated CEP degeneration and IVDD, demonstrating better repair capacity compared to natural exosomes. The findings suggest that chondrocyte-targeted exosome-mediated delivery of Nrf2 is an effective strategy for treating CEP degeneration.