Background: MiRNAs are critical in the course and prognosis of the disease and may aid in developing innovative therapies. Due to miRNAs instability and complicated environment, which includes in vivo degradation by nucleases, deregulation of miRNA expression is the hallmark of liver cancer. MiRNAs can function as oncogenes or tumor suppressors; miRNA-222 promotes tumor progression by cancer-related biological processes. MiRNAs are a novel method for cancer gene therapy due to their influence on cell signaling pathways by inhibiting or promoting many related genes. The interaction between genetics and cellular pathways contributes significantly to the onset and progression of HCC This study aims to illustrate molecular insights into the biological basis of potential anticancer efficacy of anti-microRNA in HCC cell lines Results: Normalization of dysregulated miRNAs by down-regulation block HCC cell proliferation or increase the sensitivity of liver cancer cells to chemotherapy. Effect of UTMD-mediated with anti-microRNA-222 leads to cell proliferation inhibition and cell apoptosis induction in HepG2 cells line. Inhibition of miR222 expression leads to cell cycle arrest and activation of its target genes. Conclusion: Ultrasound microbubbles are frequently utilized to investigate gene and miRNA functions. Gene delivery of miR-222 inhibitor by microbubbles/ultrasound is a new therapy and overcome chemotherapy side effects.