Lan Tingting, Li Qiushi, Yu Mingxing, Duan Xu, Ming Tao, Li Shuo, Wang Chunjiong, Zhu Yi, Shen Zhongyang, Kong Deling, Liu Yang
Research Institute of Transplant Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin, China.
Nat Commun. 2025 Aug 12;16(1):7455. doi: 10.1038/s41467-025-61965-x.
Metabolic dysfunction-associated steatotic liver disease is marked by fat accumulation and inflammation, partly due to impaired lipophagy-a cellular process in which lipid droplets are broken down through autophagy. Rubicon, a protein that inhibits this process, worsens the condition by blocking fat breakdown. Small interfering RNA molecules targeting Rubicon show therapeutic potential but face challenges such as instability and off-target effects. Here we show a dual-targeted nanoparticle system designed for efficient delivery of Rubicon-targeting small interfering RNA to liver cells. This system has a core-shell structure that ensures stability in the bloodstream and responsiveness to oxidative stress, commonly found in metabolic dysfunction-associated steatotic liver disease. Once inside the liver cells, the nanoparticles release the RNA molecules, which reduce Rubicon levels, restore lipophagy, and alleviate fatty liver buildup. This strategy offers a flexible platform for targeted gene silencing therapy in liver diseases.
代谢功能障碍相关脂肪性肝病的特征是脂肪堆积和炎症，部分原因是脂质自噬受损——脂质自噬是一种通过自噬分解脂滴的细胞过程。Rubicon是一种抑制该过程的蛋白质，它通过阻断脂肪分解使病情恶化。靶向Rubicon的小干扰RNA分子具有治疗潜力，但面临着稳定性和脱靶效应等挑战。在这里，我们展示了一种双靶向纳米颗粒系统，该系统设计用于将靶向Rubicon的小干扰RNA高效递送至肝细胞。该系统具有核壳结构，可确保在血流中稳定并对代谢功能障碍相关脂肪性肝病中常见的氧化应激作出反应。一旦进入肝细胞，纳米颗粒就会释放RNA分子，这些分子会降低Rubicon水平，恢复脂质自噬，并减轻脂肪肝的形成。该策略为肝病的靶向基因沉默治疗提供了一个灵活的平台。
