Systemic microRNA Delivery Using Polysaccharide-Coated Nanobubbles for Ultrasound-Mediated Therapy of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with the poorest prognosis and lowest survival rate. Therefore, innovative therapeutic strategies, such as nucleic acid medicines, are required. However, vascular-mediated nucleic acid delivery remains a major challenge. In particular, when targeting tumors, it is more difficult to reach deep target cells because of the complex structures within the tumor microenvironment. A combination of physical energy and stimuli-responsive carriers is expected to easily break through barriers in this microenvironment. We have developed ultrasound-responsive nanobubbles (NBs) with lipid shells that serve as gene and nucleic acid delivery tools and ultrasound contrast agents. Furthermore, we reported that NBs containing anionic lipids have high <i>in vivo</i> stability and are useful as carriers of cationic molecules. In this study, we developed a simple and versatile method for loading nucleic acids onto the surfaces of anionic NBs, which are stable <i>in vivo</i>, by coating them with the cationic polysaccharide, methyl glycol chitosan (MGC). Additionally, the utility of the MGC-coated NBs (MGC-NBs) as systemic nucleic acid delivery tools was verified. Furthermore, we attempted to deliver microRNA-145, which serves as a tumor suppressor, to tumor-bearing mouse models of TNBC and evaluated the usefulness of our method for tumor therapy.