Abstract
Extracellular vesicles (EVs), promising natural nanocarriers, face clinical hurdles like heterogeneity and immunogenicity. This study evaluates the species-specific effects and metabolic impacts of EV administration, aiming to explore their therapeutic value. EVs were isolated from rabbit and C57BL/6 mouse via ultracentrifugation, with characterization performed using transmission electron microscopy and nanoparticle tracking analysis. EVs were administered via tail vein injection to C57BL/6 mice and ob/ob mice, followed by longitudinal monitoring of blood biochemical parameters, hematological profiles, and hepatic pathological alterations. Quantitative polymerase chain reaction (qPCR) was employed to analyze EV-associated miRNA expression and associated target gene regulatory mechanisms. The study revealed that syngeneic EVs induced transient physiological fluctuations during acute exposure, with no significant alterations in blood parameters after chronic intervention. Xenogeneic EVs triggered elevated alkaline phosphatase and leukocyte imbalance, suggesting immune activation. Healthy donor EVs ameliorated hepatic steatosis in ob/ob mice, coinciding with enriched miR-26 levels in donor EVs and recipient livers. This study shows the safety benefits of syngeneic EVs, while noting the immunogenic risks of xenogeneic EV administration. Healthy donor EVs significantly reduced hepatic steatosis in obese mice, supporting the clinical translation of EV therapies.