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Abstract Background: Honey-bee venom (BV) was reported to have an anti-schistosomiasis activity; however, it expands the hepatic granuloma size in high concentration. Aim: is to overcome the high-dose problems of BV by encapsulation inside pluronic F127 (F127) nanoparticles (NPs) and preserving the sustained release of BV. Methods: The treatment efficiency of free BV, F127 NPs or BV-loaded F127 NPs was investigated via in-vitro experiments and Shistosoma (S.) mansoni infected mice. After three weeks of treatment against S. mansoni either at the juvenile or adult stages. In addition, the parasitological, immunological and histopathological parameters were evaluated. Results: The obtained data showed a reduction in the total worm burden, oogram pattern and ova count for free BV, F127 NPs or BV-loaded F127 NPs compared to infected control. The immunomodulatory function was observed by stimulation of innate immune responses (IL-33) and T helper (Th)-1 immunity (TNF-Ü) when treated with loaded NPs while F127 NPs elicited the release of IL-33, TNF-Ü, IFN-Þ, IL-10 and IL-13 compared to infected control. All tested treatments induced a reduction in both the number and the diameter of granuloma, while BV-loaded NPs provoked newly-formed bile ductules. Both F127 NPs and BV-loaded NPs induced a significant decrease in liver fibrosis area percentage with respect to the infected control. Conclusion: Free BV has a limited effect on the larval stages of S. mansoni, while BV-loaded NPs and F127 NPs showed remarkable schistosomicidal effects with lower side effects |