Extracellular vesicles in malaria: proteomics insights, in vitro and in vivo studies indicate the need for transitioning to natural human infections.

Globally, an estimated 2.1 billion malaria cases and 11.7 million malaria deaths were averted in the period 2000-2022. Noticeably, despite effective control measurements, in 2022 there were an estimated 249 million malaria cases in 85 malaria-endemic countries and an increase of 5 million cases compared with 2021. Further understanding the biology, epidemiology, and pathogenesis of human malaria is therefore essential for achieving malaria elimination. Extracellular vesicles (EVs) are membrane-enclosed nanoparticles pivotal in intercellular communication and secreted by all cell types. Here, we will review what is currently known about EVs in malaria, from biogenesis and cargo to molecular insights of pathophysiology. Of relevance, a meta-analysis of proteomics cargo, and comparisons between in vitro and in vivo human studies revealed striking differences with those few studies reported from patients. Thus, indicating the need for rigor standardization of methodologies and for transitioning to human infections to elucidate their physiological role. We conclude with a focus on translational aspects in diagnosis and vaccine development and highlight key gaps in the knowledge of EVs in malaria research.