Parasitic infectious diseases remain real and pervasive threats in many parts of the world. Parasites are affecting over a billion people worldwide and accounting for new billions of cases a year and responsible for several millions of deaths. This situation has worsened in recent decades due to the emergence and spread of drug-resistance (DR) in protozoa parasites. The importance of DR is that it makes the current treatments more likely to become ineffective in the future; thus, the burden of disease will rise. The mission of the i-NEVER REST (Investigating the role and impact of Nano-sized Extracellular VesiclEs and dRug RESisTance in protozoans) consortium is to improve global health and reduce the burden of three major diseases: malaria, leishmaniasis, and American trypanosomiasis (Chagas disease: CD). Through three complementary work packages (WP), we will generate essential knowledge of extracellular vesicles (EVs) biogenesis and content packaging, as well as mechanistic information on the development of parasitic antimicrobial resistance (AMR) mediated by EVs (WP1); profound understanding of host and parasite factors underlying the process of treatment failure and relapse (WP2); novel EV-signature profiles for detecting early (acute) and chronic infections, as well as potential relapse due to AMR (WP3).