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Trauma and surgical interventions trigger a stream of cellular, molecular, and neural signaling responses that reach and affect many tissues, and organs, especially the brain. Areas that are affected include regions that process cognitive information and behavior and these processes in the brain are dependent on signaling communication pathways between the periphery and the brain. By using an animal model that has gone through orthopedic surgery it has previously shown a response in the hippocampus which includes metabolic, morphological, and functional neuronal modifications. Emerging evidence suggests that extracellular vesicle (EV) plays an important role in intracellular tissue communication as well as periphery-to-brain signaling and hence EV-dependent signaling may provide an alternative pathway responsible for long-term changes in brain regions after surgery. The current study aims to investigate the effect of circulating human plasma EVs on cultured in vitro cells to test the toxicity and gene expression. The method included the isolation of exosomes through size exclusion chromatography (SEC), toxicity test, protein quantification, and then incubating these exosomes in the growing cell culture of hepatocarcinoma cells. Thereby isolating ribonucleic acid (RNA) from these incubated cell cultures, synthesizing complementary deoxyribonucleic acid (cDNA), and doing quantitative polymerase chain reaction (qPCR) to test the gene expression. Results showed that exosomes have an impact on gene expression mostly by downregulation and it showed no toxicity to the cells at all. The conclusion of the study remains not fully clear, and more data is needed for a further assumption, but some of the results showed similarities to earlier studies showing exosomes affect genes that are responsible for fatty acid biosynthesis and metabolism, but also genes affecting extracellular matrix (ECM)-receptor interaction by down-regulating these processes. Exosomes are a critical mediator of major intercellular communication, mostly due to their content, and further studies may have an important role in the periphery-to-brain communication causing dysfunction after surgery.