Restoring Mitochondrial Membrane Potential in Senescent Hepatocytes via Targeted NAD⁺ Precursor Delivery Using Lipid Nanoparticle Vectors
Keywords:
mitochondrial membrane potential, hepatocyte senescence, NAD⁺ repletion, lipid nanoparticle delivery, nicotinamide mononucleotide, SASP attenuation, ASGPR-targeted therapy, SIRT1/PGC-1α axis, non-alcoholic fatty liver diseaseAbstract
Senescence-associated mitochondrial dysfunction in hepatocytes represents a critical driver of non-alcoholic fatty liver disease (NAFLD) progression and systemic metabolic dysregulation. This study investigates a targeted lipid nanoparticle (LNP) delivery system loaded with nicotinamide mononucleotide (NMN) to restore mitochondrial membrane potential (ΔΨm) in replicatively senescent primary human hepatocytes. LNPs were surface-functionalized with asialoglycoprotein receptor (ASGPR)-binding galactose ligands to achieve hepatocyte-selective uptake. Cellular senescence was confirmed via p21/p53 immunostaining, β-galactosidase activity, and JC-1 mitochondrial staining. NMN-LNP treatment significantly restored ΔΨm (p < 0.001), reduced SASP cytokine secretion (IL-6, IL-8), and upregulated SIRT1/PGC-1α-mediated mitochondrial biogenesis markers. These findings identify hepatocyte-targeted NAD⁺ repletion as a tractable therapeutic strategy for mitigating senescence-driven hepatic metabolic failure in aging populations.
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