Tehran University of Medical Sciences Iranian Journal of Parasitology 1735-7020 21 2 2026 07 12 275 286 Zahra Mashhadi Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Alireza Ziyabakhsh Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Negin Farrokhiasl Deputy of Health, Ardabil University of Medical Sciences, Ardabil, Iran Fatemeh Ghaffarifar Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Behnam Mohammadi-Ghalehbin Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Shabnam Asfaram Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran Soheila Molaei Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran 2025 11 09 2026 07 12 Background: The recent increase in unresponsive cases to current treatments poses a significant challenge in the effort to discover new antileishmanial drugs. We aimed to investigate the effects of Mn2O3 NPs alone or in combination with shark cartilage extract (ShCE) on L. infantum (MCAN/ES198/LIM-877) both in vitro and in vivo. Methods: The susceptibility of promastigotes and amastigotes was evaluated using MTT and microscopy assays with different concentrations of Mn2O3 NPs alone or in combination with ShCE (Mn2O3-ShCE). The combination index (CI) was used to assess potential synergy. Cytotoxicity against J774.A1 macrophages was measured, and the selectivity index (SI) was calculated. Also, apoptosis was analyzed in promastigotes. The therapeutic and prophylactic effects were tested in BALB/c mice, and survival rates were monitored. Results: Mn2O3 NPs caused a dose-dependent decrease in proliferation of promastigotes (IC50=19.8±1.1 μg/mL) and amastigotes (IC50=29.9±0.05 μg/mL). Co‑treatment with ShCE significantly enhanced the antileishmanial activity, reducing the IC50 values of promastigotes and amastigotes. The CC50 values were 159.9±4.2 μg/mL for Mn2O3 NPs and 276.5±7.9 μg/mL for Mn2O3-ShCE. Apoptosis rates in promastigotes treated with Mn2O3 and Mn2O3-ShCE were 80.7% and 86.3%, respectively. Parasite loads in the tissues significantly decreased (P<0.001) in BALB/c mice treated with Mn2O3 NPs, and survival rates increased significantly (P<0.05). The combination with ShCE further improved outcomes, with 100% survival observed in the Mn2O3-ShCE group (P<0.01). Conclusion: These findings demonstrated a synergistic effect between Mn2O3 NPs and ShCE against L. infantum. Therefore, it may serve as a promising candidate for future development of leishmanicidal drugs. https://ijpa.tums.ac.ir/index.php/ijpa/article/view/4806 https://ijpa.tums.ac.ir/index.php/ijpa/article/download/4806/1502