Fig. 1: Targeted delivery of PPH-PEI/GalNAc@siRNA in MASH microenvironment enhances lipophagy via Rubicon suppression. | Nature Communications

Fig. 1: Targeted delivery of PPH-PEI/GalNAc@siRNA in MASH microenvironment enhances lipophagy via Rubicon suppression.

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

Fig. 1

a Schematic illustration of the multi-stage nanoparticle system, PPH-PEI/GalNAc@siRNA, designed for precise delivery of siRNA to hepatocytes in metabolic dysfunction-associated steatohepatitis (MASH). The nanoparticle comprises a ROS-responsive shell, PEI complexed with GalNAc for hepatocyte targeting, and encapsulated siRNA against Rubicon (siRubicon). b Following retrobulbar intravenous injection, the nanoparticles accumulate in the liver and are specifically activated by ROS in MASH livers. Activation triggers shell disassembly and exposes the PEI25k-GalNAc/siRubicon complex, enabling targeted delivery to hepatocytes via asialoglycoprotein receptor (ASGPR)-mediated endocytosis. c Inside hepatocytes, siRubicon silences Rubicon expression, a key negative regulator of autophagy, thereby enhancing autophagic and lipophagic flux. This leads to increased degradation of lipid droplets via lipophagy, resulting in reduced hepatic steatosis and improved metabolic outcomes in MASH. ROS reactive oxygen species, PEI polyethylenimine, GalNAc N-acetylgalactosamine, siRNA small interfering RNA, ASGPR asialoglycoprotein receptor.

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