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Mechanistic study on the alleviation of oxidative stress-induced senescence in nucleus pulposus cells by CRT and the application of its ER-targeted derivative materials

Junxian Hu,Zeyu Pang,Xiaoxiao Li,Chen Zhao,Yibo Zhu,Xiangwei Li,Huilin Zhang,Mingjie Chen,Yiyang Wang,Pei Li,Qiang Zhou

Oxidative stress-induced endoplasmic reticulum stress (ERS) plays a pivotal role in the senescence and degeneration of nucleus pulposus cells, and currently, no effective therapeutic options exist for intervertebral disc degeneration. The limited self-repair capacity of nucleus pulposus cells hampers their ability to recover, even after the removal of oxidative stressors. Consequently, the identification of cytokines capable of effectively mitigating ERS induced by cellular oxidative stress is of paramount importance for the repair of intervertebral discs. Calreticulin (CRT), an endoplasmic reticulum-resident protein, has been shown in recent studies to promote cell proliferation and collagen secretion; however, its role in intervertebral disc repair remains underexplored. This study demonstrated that CRT can repair damaged nucleus pulposus cells through two independent pathways: 1. Reducing the cell ERS condition to alleviate the rate of cell senescence; 2. Activating the FPR1/PI3K/AKT pathway to promote cell proliferation. Furthermore, a targeted endoplasmic reticulum lipid nanoparticle encapsulating CRT was successfully developed for material-based repair of damaged intervertebral discs. This novel approach provides a promising strategy for the repair of intervertebral disc degeneration.