Genotype-specific roles of small extracellular vesicles in modulating metronidazole resistance in Giardia lamblia

Giardia lamblia, a eukaryotic intestinal parasite, produces small extracellular vesicles (sEVs) as a conserved evolutionary mechanism. This study investigates the functional role of sEVs in transferring drug-resistance traits among parasites. sEVs derived from metronidazole (MTZ)-resistant clones are shown to modify the expression of enzymes involved in MTZ metabolism and the production of reactive oxygen species (ROS) in recipient wild-type parasites. These changes significantly alter the drug sensitivity of recipient parasites. The transfer efficiency and phenotypic impact vary depending on the genetic background of the isolates, highlighting a genotype-specific mechanism. Our findings reveal that sEVs act as mediators of phenotypic adaptation in G. lamblia, enhancing parasite survival under drug-induced stress. This study underscores the importance of sEVs in drug-resistance dynamics and provides a basis for exploring therapeutic interventions targeting EV-mediated resistance in giardiasis. Highlights In briefO_LISmall extracellular vesicles (sEVs) from Giardia lamblia mediate genotype-specific MTZ resistance transfer. C_LIO_LISmall extracellular vesicles from drug-resistant clones (RsEVs) alter enzyme expression and reactive oxygen species (ROS) production in recipient trophozoites. C_LIO_LIThe genetic background of G. lamblia isolates influences the effectiveness of resistance transfer. C_LIO_LIFindings provide insights into resistance mechanisms and potential targets for new giardiasis therapies. C_LI