Nanoceria drive stem cell hepatic differentiation and microenvironment remodeling for acute liver failure therapy.

Stem cell-derived hepatocyte therapy holds great potential for treating acute liver failure (ALF) by rapidly restoring liver function and stimulating regeneration. However, significant challenges remain in efficiently driving stem cells toward a hepatic lineage and ensuring transplanted cell survival and functionality in the hostile, injured liver microenvironment. To overcome these hurdles, we developed a novel ceria nanoparticle@microRNA complex that facilitates hepatic differentiation of mesenchymal stem cells. We show that ceria nanozymes synergize with microRNA-122 to enhance hepatic differentiation by maintaining redox homeostasis and boosting mitochondrial biogenesis via TCF7L2 suppression, providing direct evidence that ceria nanoparticles can promote stem cell hepatic lineage commitment. Furthermore, we coated the resulting induced hepatocyte-like cells with a cerium-tannic acid metal-phenolic network, which protected the cells from oxidative damage under liver failure conditions. In a carbon tetrachloride-induced acute liver failure mouse model, this integrated strategy significantly restored liver functions and promoted tissue regeneration. Overall, this study establishes a new bio-nano approach for stem cell-based liver therapy and offers fundamental insights into how bioactive nanomaterials can orchestrate stem cell differentiation and microenvironment remodeling, highlighting a conceptually innovative strategy with translational potential.