AKG-UO-1 is an innovative ionizable lipid engineered for targeted nucleic acid delivery, exhibiting exceptional hepatic tropism and a high affinity for metabolically active tissues. Leveraging an alpha-ketoglutarate (AKG)-inspired design, it capitalizes on the liver’s high metabolic demand to achieve precise parenchymal accumulation via systemic injection. Crucially, AKG-UO-1 selectively homing into diseased or lipid-accumulated microenvironments, where it enhances endosomal escape and mRNA translation. Its unique degradation pathway actively synergizes with host cells to alleviate metabolic stress and maintain mitochondrial homeostasis, making it an ideal candidate for treating metabolic liver diseases and fatty liver disorders.