Chitosan–PLGA Hybrid Nanocarriers Enhance Therapeutic Delivery of Doxorubicin for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal malignancies worldwide, with limited therapeutic outcomes due to systemic toxicity and suboptimal efficacy of conventional chemotherapeutics such as doxorubicin (DOX). In this study, we formulated and standardized DOX-loaded chitosan/poly (lactic-co-glycolic acid) nanoparticles (DLCNs) via a nanoprecipitation method and evaluated their therapeutic potential in a diethylnitrosamine (DEN)-induced Wistar rat model of HCC. Physicochemical analyses confirmed nanoscale size, favorable zeta potential, and high encapsulation efficiency, while Fourier-transform infrared spectroscopy (FTIR) verified polymer–drug interactions. Biochemical analysis revealed that DLCNs significantly normalized elevated liver function markers (Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), restored serum α-fetoprotein (AFP) to near-control levels, and reduced lipid peroxidation compared with free DOX and DEN controls. Antioxidant profiling demonstrated marked recovery of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), indicating restoration of hepatic redox balance. Histopathological evaluation further corroborated these findings, showing recovery of hepatic lobular architecture and reduction in necrosis and inflammatory infiltrates in DLCN-treated Wistar Albino rats, while free DOX groups exhibited hepatocellular damage. Overall, the results demonstrate that encapsulating DOX in a chitosan/PLGA nanocarrier improves therapeutic efficacy, mitigates hepatotoxicity, and enhances antioxidant defense, establishing DLCNs as a favorable candidate for HCC.