Deliver CEBPE via cartilage targeting Lipid nanoparticle to block CEBPE-LTF-STAT3 positive feedback loop for efficient treatment of cartilage endplate degeneration

Deliver CEBPE via cartilage targeting Lipid nanoparticle to block CEBPE-LTF-STAT3 positive feedback loop for efficient treatment of cartilage endplate degeneration

Intervertebral disc degeneration (IVDD) is recognized as a significant underlying factor contributing to clinical neck and low back pain. The cartilaginous endplates (CEP) serve as a selectively permeable barrier, which is essential for maintaining the internal homeostasis of the intervertebral disc...

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Main Authors: Jiangminghao Zhao, Peichuan Xu, Tao Li, Jinghong Yuan, Wenrui Zhao, Rui Ding, Guoyu Yang, Jiajun Xie, Guanfeng Huang, Zhidong Peng, Xinxin Miao, Xigao Cheng
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Materials Today Bio
Subjects:
Intervertebral disc degeneration
Lipid nanoparticle
Cartilage targeting
CEBPE
LTF
JAK2/STAT3 inflammatory signaling pathway
Online Access:http://www.sciencedirect.com/science/article/pii/S2590006425005976
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Summary:Intervertebral disc degeneration (IVDD) is recognized as a significant underlying factor contributing to clinical neck and low back pain. The cartilaginous endplates (CEP) serve as a selectively permeable barrier, which is essential for maintaining the internal homeostasis of the intervertebral disc (IVD). Dysfunction of the CEP is closely related to the initiation and progression of IVDD. In this paper, we demonstrate that CCAAT enhancer-binding protein ε (CEBPE) is crucial for the degeneration of the CEP. We observed a significant downregulation of CEBPE in CEP degeneration. The deficiency of CEBPE leads to inflammation, degradation of the extracellular matrix (ECM), and calcification of endplate chondrocytes (EPCs). Conversely, overexpression of CEBPE mitigates these detrimental processes. Mechanistically, CEBPE deficiency down-regulates the transcription level of lactoferrin (LTF), which in turn activates the JAK2/STAT3 inflammatory signaling pathway, and STAT3 inhibits the transcription of CEBPE. These findings unveil a previously unidentified positive feedback loop, CEBPE-LTF-STAT3, that modulates EPCs degeneration. Importantly, a lipid nanoparticle targeting chondrocytes for the efficient delivery of a CEBPE-overexpressing plasmid significantly reduced ECM degradation and the calcification process in CEP, substantially attenuating the progression of IVDD. This highlights promising targets and effective strategies for mitigating the impact of IVDD.
ISSN:2590-0064

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