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MicroRNAs (miRNAs) are involved in the pathogenesis of several cancers including skin squamous cell carcinoma (sSCC), and miR-134 is reported to possess tumor inhibition properties. The present study is an attempt to study the mechanistic role and antitumor property of miR-134 in sSCC. For this purpose, α-tocopherol PEG 1000 succinate (TPGS)-based PEGylated liposome was formulated and encapsulated with miR-134 (TP-miR-LP). CCK-8 assay results showed that miR-134 exhibited a concentration-dependent decrease in the cell viability of A-431 cells. Importantly, TPGS-based TP-miR-LP showed significantly (p < 0.05) lower cell viability compared with that of miR-134-loaded PEGylated liposome (miR-LP). Western blot analysis clearly indicates the specific targeting ability of miR-134 (TP-miR-LP) towards the Forkhead Box M1 (FOXM1) in the cancer cells. The apoptosis rate of the cells was significantly increased in TP-miR-LP (~ 38%) than that of miR-LP (~ 15%), respectively with significant inhibition of cell migration. Importantly, tumors treated with TP-miR-LP grew significantly slower compared with that of any other formulation group in the xenograft animal model. Present results clearly demonstrate the tumor suppressive effect of miR-134 through the downregulation of FOXM1 which subsequently blocks the downstream signaling pathways. These findings suggest the translational potential of miR-134 towards designing formulation strategies for sSCC treatment. Graphical abstract.