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

Tingting Lan, Qiushi Li, Mingxing Yu, Xu Duan, Tao Ming, Shuo Li, Chunjiong Wang, Yi Zhu, Zhongyang Shen (), Deling Kong () and Yang Liu ()
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Tingting Lan: Nankai University
Qiushi Li: Nankai University
Mingxing Yu: Nankai University
Xu Duan: Nankai University
Tao Ming: Nankai University
Shuo Li: Nankai University
Chunjiong Wang: Tianjin Medical University
Yi Zhu: Tianjin Medical University
Zhongyang Shen: Nankai University
Deling Kong: Nankai University
Yang Liu: Nankai University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61965-x

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