Acute liver injury (ALI), characterized by rapid hepatocyte damage induced by drugs, toxins, or viral infections, lacks clinically effective targeted therapies. Usually, the impaired hepatocytes significantly inhibit the uptake of medicines, leading to poor bioavailability and therapeutic outcome. Herein, a combination of hepatocyte growth factor (HGF) and interleukin-22 (IL-22) mRNAs delivered by N-acetylgalactosamine modified lipid nanoparticles (GalNAc-LNP) was developed to treat ALI. Tetra-antennary GalNAc cholesterol conjugate was first synthesized and incorporated into conventional LNP to encapsulate HGF/IL-22 mRNAs. After that, ALI mice model was applied to test the delivery effect of GalNAc-LNP. It was found that the GalNAc-LNP overcame delivery barriers caused by necrosis and inflammation, increasing protein expression of the encapsulated mRNA in the liver by 121.0%, owing to GalNAc- ASGPR targeting. Importantly, HGF/IL-22 mRNAs combination encapsulated within GalNAc-LNP markedly reduced necrotic foci, promoted hepatocyte regeneration, alleviated inflammatory response and accelerated recovery of liver function. The results demonstrated the synergistic effects of HGF-driven hepatocyte proliferation and IL-22-mediated inhibition of hepatic inflammation. Taken together, HGF/IL-22 mRNAs delivered by GalNAc-LNP possesses dual-target synergistic therapeutic output, holding potential for the treatment of ALI.
