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Despite its high potential, non‐viral gene therapy of cancer remains challenging due to inefficient nucleic acid delivery. Ultrasound (US) with microbubbles (MB) can open biological barriers and thus improve DNA and mRNA passage. Polymeric MB are an interesting alternative to clinically used lipid‐coated MB because of their high stability, narrow size distribution, and easy functionalization. However, besides choosing the ideal MB, it remains unclear whether nanocarrier‐encapsulated mRNA should be administered separately (co‐administration) or conjugated to MB (co‐formulation). Therefore, the impact of poly(n‐butyl cyanoacrylate) MB co‐administration with mRNA‐DOTAP/DOPE lipoplexes or their co‐formulation on the transfection of cancer cells in vitro and in vivo is analyzed. Sonotransfection improved mRNA delivery into 4T1 breast cancer cells in vitro with co‐administration being more efficient than co‐formulation. In vivo, the co‐administration sonotransfection approach also resulted in higher transfection efficiency and reached deeper into the tumor tissue. On the contrary, co‐formulation mainly promoted transfection of endothelial and perivascular cells. Furthermore, the co‐formulation approach is much more dependent on the US trigger, resulting in significantly lower off‐site transfection. Thus, the findings indicate that the choice of co‐administration or co‐formulation in sonotransfection should depend on the targeted cell population, tolerable off‐site transfection, and the therapeutic purpose. [ABSTRACT FROM AUTHOR]