The safe and efficient delivery of chemicals and biologics remains crucial for liver disease therapy. In this study, we developed a targeted drug delivery system utilizing a galactose-modified erythrocyte membrane coating technique and drug liposome nanoparticles, which were further optimized using orthogonal experiments and response surface analysis. The specificity, precision, accuracy, and stability exhibited satisfactory performance in bioanalytical analysis. Specifically, targeting ligands (Gal-DSPE-PEG3400) were efficiently inserted into red blood cell (RBC) membranes using a facile insertion method. When Gal-DSPE-PEG3400-RBC was fused with fenofibrate liposome nanoparticles (FNB-Lip) by co-extrusion, the resulting galactose-modified erythrocyte membrane fusion liposome nanoparticles (Gal-RBC-FNB-Lip) showed long-term stability, excellent biocompatibility, prolonged retention time, and superior liver accumulation and therapeutic efficacy. These qualities make it suitable for effective drug delivery. The findings of this study will provide a fundamental basis for research and development of liver-targeted drugs and offer novel insights into the treatment of clinical liver diseases.