Lipid Nanoparticles Delivering ClpP‐mRNA Suppress Pyroptosis and Senescence in Intervertebral Disc Degeneration via mTOR/BNIP3‐Activated Mitophagy

ABSTRACT Intervertebral disc degeneration (IDD) is a predominant cause of low back pain, significantly impacting quality of life. Mitochondrial fitness is essential in the progression of IDD, as it regulates cellular senescence and pyroptosis. This study investigates the role of mitochondrial caseinolytic protease P (ClpP) in alleviating senescence and pyroptosis in nucleus pulposus cells (NPCs) through the enhancement of mitophagy. The significance of ClpP in IDD was established using clinical disc samples and rat models. We developed a lipid nanoparticle (LNP)‐encapsulated mRNA encoding ClpP (LNP–ClpP) to boost ClpP expression in NPCs under hypoxic conditions. In vitro assays and histological analyses demonstrated that ClpP activates mitophagy via the mTOR/BNIP3 pathway, leading to a significant reduction in senescence markers (p16 and p21) and pyroptosis markers (NLRP3 and caspase‐1 p20) in hypoxia‐exposed NPCs. In vivo experiments demonstrated that LNP–ClpP treatment alleviated the loss and fibrosis of nucleus pulposus tissue induced by fibrous puncture. Furthermore, immunohistochemical results indicated that LNP–ClpP reduced the expression of NLRP3 and p21 in the nucleus pulposus tissues of degenerated discs, underscoring the beneficial effect of LNP–ClpP in ameliorating disc degeneration. Overall, this study positions ClpP as a promising therapeutic target for IDD. The development of LNP‐based delivery systems for ClpP mRNA represents an innovative non‐surgical approach to augment mitochondrial function, thereby presenting a transformative therapeutic strategy for spinal degenerative disorders.