2. Academic Validation
  3. A multifaceted strategy for intra- and extracellular nucleic acid regulation to alleviate intervertebral disc degeneration

A multifaceted strategy for intra- and extracellular nucleic acid regulation to alleviate intervertebral disc degeneration

  • Nat Commun. 2025 Aug 26;16(1):7936. doi: 10.1038/s41467-025-63194-8.
Lan Zhao # 1,  Kaiyu Liang # 2,  Wenqiang Cheng # 1,  Xizhuo Zhou 1,  Libin Yang 1,  Xinning Mao 1,  Weihui Qi 1,  Hongting Jin 3 4,  Wei Zhang 5,  Hao Pan 6,  Dong Wang 7
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
  • 2 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. kaiyu_liang@zju.edu.cn.
  • 3 Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China. hongtingjin@zcmu.edu.cn.
  • 4 Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China. hongtingjin@zcmu.edu.cn.
  • 5 Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China. volcano8060@163.com.
  • 6 Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China. harper1966@alu.zcmu.edu.cn.
  • 7 Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China. hz-wdong@alu.zcmu.edu.cn.
  • # Contributed equally.
PMID: 40858573 DOI: 10.1038/s41467-025-63194-8
Abstract

Abnormal accumulation of both intracellular and extracellular free nucleic acids drives chronic inflammation in intervertebral disc degeneration (IVDD). Despite the development of numerous minimally invasive treatments for IVDD, systematic approaches targeting the chronic inflammation mediated by both nucleic acid types are lacking. We propose a dual clearance strategy that inhibits mitochondrial DNA release inside nucleus pulposus cells while removing extracellular DNA from the disc microenvironment. Using single-cell Sequencing and clinical samples, we revealed how both nucleic acid types drive inflammation. We then developed a targeted nanovesicle system delivering a mitochondrial membrane-stabilizing small molecule to block DNA leakage and inflammatory signaling, along with a hydrogel that captures extracellular DNA to prevent immune activation. In a rat model, this approach significantly slowed disease progression. This targeted dual nucleic acid clearance strategy provides a approach for treating IVDD and offers a theoretical framework for addressing Other nucleic acid-related inflammatory diseases.

Figures
Products