Peptide-Functionalized Liposomal Nanocarriers for Targeted Therapy of Liver Fibrosis and Hepatocellular Carcinoma: Design, Mechanisms, and Clinical Prospects

Liver fibrosis and hepatocellular carcinoma (HCC) remain major global health burdens, in part due to limited drug specificity, off-target toxicity, and the complex hepatic microenvironment. Peptide-functionalized liposomal nanocarriers have emerged as a promising approach to enhance cell-selective drug delivery to activated hepatic stellate cells in fibrosis and malignant hepatocytes in HCC. This review critically examines recent progress in peptide-guided liposomal systems, focusing on design strategies, receptor-mediated targeting mechanisms, and translational considerations. Key peptide ligands, including cyclic RGD peptides targeting integrins αvβ3/αvβ5, GE11 for epidermal growth factor receptor, and transferrin receptor-binding peptides, are discussed in relation to their roles in promoting receptor-mediated endocytosis. Liposome fabrication methods and ligand conjugation chemistries are evaluated for their impact on stability, ligand presentation, and in vivo biodistribution. Preclinical evidence demonstrating improved drug accumulation, reduced fibrosis markers, and suppression of tumor growth is summarized alongside current limitations including receptor heterogeneity, extracellular matrix barriers, and manufacturing scalability. Finally, emerging directions such as stimuli-responsive and theranostic liposomes as well as combination strategies with immunomodulatory therapies are highlighted. By integrating mechanistic insight with design and translational perspectives, this review identifies key opportunities and the remaining hurdles in advancing peptide-targeted liposomal nanomedicines for liver disease.