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

Area of Science:

• Hepatology
• Molecular Biology
• Nanomedicine

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) involves liver fat accumulation and inflammation.
• Impaired lipophagy, the breakdown of lipid droplets via autophagy, contributes to MASLD pathogenesis.
• Rubicon protein inhibits lipophagy, exacerbating fat buildup in the liver.

Purpose of the Study:

• To develop a novel nanoparticle system for targeted delivery of small interfering RNA (siRNA) against Rubicon.
• To overcome the instability and off-target effects associated with traditional siRNA delivery.
• To evaluate the therapeutic potential of this system in alleviating fatty liver disease.

Main Methods:

• Design of a dual-targeted nanoparticle with a core-shell structure for enhanced stability and oxidative stress responsiveness.
• Encapsulation of Rubicon-targeting siRNA within the nanoparticles for targeted delivery to liver cells.
• Assessment of nanoparticle uptake, Rubicon level reduction, lipophagy restoration, and reduction of hepatic steatosis in vitro and/or in vivo models.

Main Results:

• The dual-targeted nanoparticles demonstrated stability in circulation and responsiveness to oxidative stress.
• Efficient delivery of siRNA to liver cells was achieved, leading to reduced Rubicon protein levels.
• Restoration of lipophagy and significant alleviation of fat accumulation in the liver were observed.

Conclusions:

• A novel nanoparticle system effectively delivers Rubicon-targeting siRNA to liver cells, addressing key challenges in gene silencing therapy.
• This strategy shows promise for treating metabolic dysfunction-associated steatotic liver disease by restoring lipophagy and reducing hepatic steatosis.
• The developed nanoparticle platform offers a flexible approach for targeted gene silencing in various liver conditions.