Beyond the mouse: organoids, spheroids, and organs-on-chips as the (inevitable) future of malaria research?

Malaria remains a major global health threat, causing substantial clinical and socioeconomic burdens in endemic regions. Despite important advances in control strategies, progress is increasingly challenged by antimalarial drug resistance, widespread insecticide resistance, diagnostic escape, and adaptive changes in vector behavior. In this context, robust experimental models are essential to improve understanding of parasite biology, host-pathogen interactions, and therapeutic responses. Murine malaria models remain central to preclinical research because they are accessible, genetically tractable, cost-effective, and well suited to controlled studies of immunity, pathophysiology, transmission, and drug efficacy. Continuous refinement of these models through parasite and host genetic engineering, including transgenic parasites and modified or humanized mouse strains, has further expanded their experimental value. However, murine models do not fully reproduce human malaria. Key interspecies differences in parasite biology, antigenic variation, cytoadherence, tissue tropism, placental structure, blood-brain barrier interactions, and disease kinetics limit direct translation, particularly for severe, cerebral, placental, and relapsing malaria caused by Plasmodium falciparum and Plasmodium vivax. These limitations underscore the need for complementary human-relevant platforms. Micro physiological systems are emerging as a critical addition to the malaria research toolbox. Spheroids offer scalable three-dimensional models for medium-throughput studies; organoids reproduce essential structural and functional features of human tissues such as the liver, brain, placenta, and vasculature; and organ-on-chip systems incorporate flow, shear stress, and multicellular interfaces to better model sequestration, endothelial activation, barrier dysfunction, liver-stage infection, and drug responses. Rather than replacing murine models, these technologies complement them by bridging the gap between reductionist in-vitro assays and human disease biology, while supporting the principles of replacement, reduction, and refinement. This narrative review examines the current landscape of murine malaria models, their major contributions and translational limitations, and the growing importance of micro physiological systems, with their limitations, in next-generation malaria research.