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Cryptosporidiosis is a worldwide health problem that results in an economic loss. The disease is caused by the protozoan Cryptosporidium spp. Individuals with suppressed immunity, like those with organ transplantation, cancer and human immunodeficiency virus syndrome, suffer from the infection that may lead to the death. Nitazoxanide (NTZ) is the approved FDA treatment for cryptosporidiosis in immunocompetent individuals. There is an urgent need to find a new natural treatment that can replace NTZ in immunosuppressed hosts. The study aimed to use grape seed extract loaded chitosan nanoparticles (GSEx-CHNPs) in treatment of cryptosporidiosis in immunosuppressed male mice. GSEx was prepared by the alcoholic extraction method followed by the identification of its bioactive components. GSEx-CHNPs were synthesized by ionic gelation method and physically characterized then their activities were examined in vitro. The experimental groups, included immunocompetent and immunosuppressed groups, was treated with NPs for 14 days post infection (PI). The results showed the presence of many phenolic compounds in the GSEx. GSEx-CHNPs significantly improved the loss in animals body weight, cleared the infection and amolerated the serum cytokines levels. GSEx-CHNPs showed anti-cryptosporidial activity especially in immunosuppressed mice model. Where, it amolerated the disturbance in the cytokine profile leading to an anti-inflammatory response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)