Recent Advances in Natural and Nanoparticle-Based Therapies for Naegleria fowleri Infections

Primary amoebic meningoencephalitis (PAM), caused by Naegleria fowleri, remains an aggressively fatal infection with often ineffectual treatment avenues. This study reviews the antiamoebic efficacy of natural-derived compounds, including plant-based, marine-sourced, and nano-conjugated metabolites, bringing light to their potential as next-generation therapeutics. Notably, plant-derived kaempferol and diosgenin were found to induce programmed cell death (PCD) in N. fowleri via mitochondrial signalling and production of reactive oxidative species (ROS), without the added toxicity to normal human cell lines. Terpenes such as thymol and forskolin effectively targeted both trophozoites and cysts by disrupting intracellular signalling and cell membrane integrity. The ability to cross the blood-brain barrier (BBB) was exhibited by marine-derived oxasqualenoids and sesquiterpenes a key requirement for effective PAM therapy, with the added ability to induce apoptosis in trophozoites. These compounds interfere with critical pathogenic mechanisms, including phagocytosis, adhesion, and protease activity highlighting their potential for multi-targeted therapy. Compared to current PAM treatments, which are limited by toxicity and poor central nervous (CNS) penetration, these natural compounds offer a safer and potentially more effective alternative. Additionally, nanoconjugation significantly enhanced the compound bioavailability, brain-targeting, and retention, further amplifying their therapeutic potential. This comprehensive review aims to bring to the apogee, the scientific importance of these findings and lays the foundation for future drug development strategies that harness the structural diversity and mechanistic specificity of natural products for treating PAM.