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Sofosbuvir is a potent HCV NS5B nucleotide polymerase inhibitor with broad genotypic coverage and low risk of developing drug resistance. While clinical studies have provided the effectiveness of sofosbuvir for treatment of patients with hepatitis C virus genotype 4 (HCV-4), however, many side-effects were reported. To reduce those side effects and improve the antiviral activity of the drug, sofosbuvir was encapsulated into chitosan nanoparticles (CNPs) to produce sofosbuvir encapsulated chitosan nanoparticles (SCNPs). 3D Molecular simulation and dynamics were made for sofosbuvir and SCNPs to evaluate the active sites of HCV-4 NS3 protease, NS5B polymerase and HCV helicase relative to both their catalytic activities and drug susceptibilities. The produced SCNPs were finally evaluated on hepatoblastoma cells (Huh7) for their antiviral efficiency. Results: The suggested chemical structure for SCNPs was confirmed by FTIR. The average particle size and surface charge of SCNPs were 137 +/- 34 nm and 29 +/- 9.6 mV respectively. The Encapsulation efficiency was 80% and the loading efficiency was 6%. The binding affinity of SCNPs with HCV-4 NS3, NS5B and NS5A were -156.512, -154.603 and -131 respectively. But for sofosbuvir were -127.581, -131.535 and -167 respectively based on the MolDock score. The treatment of HCV- 4 infected Huh7 cells with up to 100 {\mu}M of SCNPs neither showed significant cytotoxic nor genotoxic effects after 48 hours of cell exposure. Finally, a complete disappearance of HCV RNA was seen after 24 hours of exposure to 100 {\mu}M of SCNPs when compared with the untreated cells., Comment: 27 pages, & figures, Antiviral Therapies II, American Society for Virology (ASV), July, 2018