A Redox Homeostasis Modulatory Hydrogel with GLRX3 + Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence

作者：Can Liu, Lei Fan, Ming Guan, Qiangqiang Zheng, Jiale Jin, Xinchang Kang, Zhongyang Gao, Xiaoqian Deng, Yifan Shen, Guangyu Chu, Jingyao Chen, Zhiqiang Yu, Lei Zhou, Yue Wang · 发表于：ACS Nano · 年份：2023 · DOI：10.1021/acsnano.3c01713 · 被引用次数：87 · 研究领域：Spine and Intervertebral Disc Pathology、Spinal Cord Injury Research、Cervical and Thoracic Myelopathy

Characterized by nucleus pulposus (NP) cell senescence and extracellular matrix (ECM) degradation, disc degeneration is a common pathology for various degenerative spinal disorders. To date, effective treatments for disc degeneration are absent. Here, we found that Glutaredoxin3 (GLRX3) is an important redox-regulating molecule associated with NP cell senescence and disc degeneration. Using a hypoxic preconditioning method, we developed GLRX3 + mesenchymal stem cell-derived extracellular vehicles (EVs-GLRX3), which enhanced the cellular antioxidant defense, thus preventing reactive oxygen species (ROS) accumulation and senescence cascade expansion in vitro . Further, a disc tissue-like biopolymer-based supramolecular hydrogel, which was injectable, degradable, and ROS-responsive, was proposed to deliver EVs-GLRX3 for treating disc degeneration. Using a rat model of disc degeneration, we demonstrated that the EVs-GLRX3-loaded hydrogel attenuated mitochondrial damage, alleviated the NP senescence state, and restored ECM deposition by modulating the redox homeostasis. Our findings suggested that modulation of redox homeostasis in the disc can rejuvenate NP cell senescence and thus attenuate disc degeneration.