Visceral Leishmaniasis (VL), a systemic disease caused by the protozoan parasite Leishmania donovani, represents a significant global health challenge as the second most lethal parasitic infection after malaria. Transmitted through the bites of infected female phlebotomine sandflies (principally Phlebotomus argentipes within the Indian subcontinent), the pathogen proliferates within the host’s mononuclear phagocyte system, primarily affecting the spleen, liver, and bone marrow. Current conventional therapeutics are heavily constrained by severe clinical limitations,
including systemic toxicity, poor bioavailability, rapid clearance rates, and the emergence of drug resistance. Although polymeric and lipid-based nanoparticles have been explored to address these issues, their clinical translation is hindered by storage instability, limited payload capacities, and
intricate manufacturing protocols. In contrast, metal-based nanocarriers, particularly silver nanoparticles, offer distinct advantages such as intrinsic reactive oxygen species (ROS) generation, enhanced stability, a high surface-area-to-volume ratio, and options for controlled, targeted
delivery. To optimise cell-specific delivery, the surface of these silver nanoparticles can be functionalized with targeting ligands (such as mannose or specific amino acids like histidine) to direct them precisely to macrophage surface receptors, thereby enhancing intracellular
internalisation. Prior bioinformatic screening successfully identified novel chemical compounds capable of inhibiting the folate pathway, particularly the DHFR-TS and PTR1 of L. donovani. Following the acquisition of statistically significant and efficient results from these predictive
studies, these specific ligands were functionalized onto the nanoparticles, and current research is focused on evaluating their therapeutic efficacy against active L. donovani strains.