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Leishmaniasis encompasses an array of clinical syndromes ranging from self-resolving cutaneous to mucocutaneous andsevere visceral manifestations, which result from infection of macrophages in the dermis, the naso-oropharyngeal mucosa,and the reticuloendothelial system, respectively. Cutaneous and mucosal leishmaniasis can cause substantial morbidity, whereasvisceral leishmaniasis (VL) or kala-azar is systemic and can be life threatening. In the absence of effective vector control measuresand vaccines, chemotherapy remains the mainstay in the control of VL, a neglected disease of poverty. There is a pressing needfor alternate rescue therapy due to escalating drug refractoriness, coupled with adverse effects, emergence of HIV co-infection,and resurfacing in the form of post kala-azar dermal leishmaniasis after apparent cure. The Leishmania parasites evade hostdefensive machinery, encumbering antigen presentation to T cells, and eventually leading to subversion of cell-mediatedimmunity (CMI). Thus, a promising therapeutic approach would entail administration of antileishmanial compounds, whichcan concurrently rejuvenate an effective T-helper-1 response, for subsequent macrophage activation to eliminate intracellularLeishmania amastigotes.Sesquiterpene lactones exhibit a wide spectrum of antimicrobial activities. Artemisinin belongs to a class of sesquiterpeneswith potent antileishmanial activity but has limited access to infected cells, being a highly lipophilic molecule. Association ofartemisinin with liposome is a desirable strategy to elude the problem of poor accessibility, thereby ameliorating its efficacyin a murine model of experimental VL. Nanoliposomal artemisinin (NLA) was prepared by thin film hydration methodand optimized using Box-Behnkehn design. The NLA was free from concomitant signs of toxicity, both ex vivo on murinemacrophages as well as in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of L. donovaniamastigotes ex-vivo as well as in vivo. Protection coincided with modulation of CMI as evidenced by the positive delayed typehypersensitivity response, lymphoproliferation after antigen recall in vitro, induction of Th1 signature cytokines and protectiveantibody isotypes. This nanoliposomal drug delivery system for artemisinin with synergistic Th1 immunopotentiation mayserve as a promising alternative intervention against VL.