可电离的共酶工程脂质/纤维微复合体促进核糖体翻译,以改善退行性疾病的mRNA疗法
Shifeng Ling1, Yixiang Zhang2, Yanyang Chen1
1Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China.
Advanced materials (Deerfield Beach, Fla.)
|October 8, 2025
概括
用可离子化辅酶Q10 (iCoQ10) 设计的新型微复合体恢复了线粒体功能并增强了mRNA翻译,改善了治疗衰老和退行性疾病的疗法.
科学领域:
- 生物医学工程 生物医学工程
- 分子生物学分子生物学
- 衰老研究研究 衰老研究
背景情况:
- 线粒体功能障碍抑制了核糖体翻译,这是衰老和退行性疾病的关键因素,阻碍了mRNA治疗的有效性.
- 目前的mRNA疗法由于老化或生病细胞的翻译受损而面临局限性.
研究的目的:
- 开发新的可电离辅酶Q10 (iCoQ10) 工程脂质/纤维微复合体 (iCLNP@SF),以恢复线粒体-核糖体轴和增强mRNA翻译.
- 评估iCLNP@SF在衰老细胞和退行性疾病的体内模型中的疗效.
主要方法:
- 合成的iCoQ10工程脂质纳米颗粒 (iCLNP),通过多多巴胺修饰的短纤维 (SF) 稳定,用于局部管理.
- 在衰老细胞中评估了体外疗效,测量了线粒体代谢和mRNA转化.
- 在体内进行的研究使用雄性和骨缺陷小鼠模型,分别输送Gas6和Runx2mRNA.
主要成果:
- iCLNP@SF在衰老细胞中证明了线粒体代谢和mRNA翻译的协同增强.
- 机制研究表明,iCLNP稳定了线粒体膜潜力,抑制了cGAS-STING激活,并减少了eIF2α酸化.
- 在体内,iCLNP@SF输送的Gas6mRNA增加了毛囊密度约50%,Runx2mRNA输送增加了新骨形成约40%,超过了传统的脂质纳米颗粒 (LNP).
结论:
- iCLNP@SF有效地恢复线粒体-核糖体轴,增强mRNA翻译和克服当前mRNA疗法的局限性.
- 这一策略显示出治疗与年龄相关的退行性疾病的巨大潜力,包括脱发和骨缺陷.
- 开发的微复数系统为提高基于mRNA的疗法的疗效提供了一个有希望的方法.
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