Zhao Lan, Liang Kaiyu, Cheng Wenqiang, Zhou Xizhuo, Yang Libin, Mao Xinning, Qi Weihui, Jin Hongting, Zhang Wei, Pan Hao, Wang Dong
Department of Orthopedic Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nat Commun. 2025 Aug 26;16(1):7936. doi: 10.1038/s41467-025-63194-8.
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.
细胞内和细胞外游离核酸的异常积累驱动椎间盘退变（IVDD）中的慢性炎症。尽管已经开发出多种针对IVDD的微创治疗方法，但缺乏针对由这两种核酸类型介导的慢性炎症的系统方法。我们提出了一种双重清除策略，该策略可抑制髓核细胞内线粒体DNA的释放，同时从椎间盘微环境中清除细胞外DNA。通过单细胞测序和临床样本，我们揭示了这两种核酸类型如何驱动炎症。然后，我们开发了一种靶向纳米囊泡系统，该系统可递送一种稳定线粒体膜的小分子以阻断DNA泄漏和炎症信号传导，同时还开发了一种水凝胶来捕获细胞外DNA以防止免疫激活。在大鼠模型中，这种方法显著减缓了疾病进展。这种靶向双重核酸清除策略为治疗IVDD提供了一种方法，并为解决其他与核酸相关的炎症性疾病提供了理论框架。
