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<p>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.</p>

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Dual-targeted siRubicon delivery strategy triggers hepatocellular lipophagy for mitigating liver steatosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月12日

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  • Tingting Lan,
  • Qiushi Li,
  • Mingxing Yu,
  • Xu Duan,
  • Tao Ming,
  • Shuo Li,
  • Chunjiong Wang,
  • Yi Zhu,
  • Zhongyang Shen,
  • Deling Kong,
  • Yang Liu

摘要

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.