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Nanomotor-Enabled pH-Responsive Intracellular Delivery of Caspase-3: Toward Rapid Cell Apoptosis

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journal contribution
posted on 03.05.2017, 00:00 by Berta Esteban-Fernández de Ávila, Doris E. Ramírez-Herrera, Susana Campuzano, Pavimol Angsantikul, Liangfang Zhang, Joseph Wang
Direct and efficient intracellular delivery of enzymes to cytosol holds tremendous therapeutic potential while remaining an unmet technical challenge. Herein, an ultrasound (US)-propelled nanomotor approach and a high-pH-responsive delivery strategy are reported to overcome this challenge using caspase-3 (CASP-3) as a model enzyme. Consisting of a gold nanowire (AuNW) motor with a pH-responsive polymer coating, in which the CASP-3 is loaded, the resulting nanomotor protects the enzyme from release and deactivation prior to reaching an intracellular environment. However, upon entering a cell and exposure to the higher intracellular pH, the polymer coating is dissolved, thereby directly releasing the active CASP-3 enzyme to the cytosol and causing rapid cell apoptosis. In vitro studies using gastric cancer cells as a model cell line demonstrate that such a motion-based active delivery approach leads to remarkably high apoptosis efficiency within a significantly shorter time and with a lower amount of CASP-3 compared to other control groups not involving US-propelled nanomotors. For instance, the reported nanomotor system can achieve 80% apoptosis of human gastric adenocarcinoma cells within only 5 min, which dramatically outperforms other CASP-3 delivery approaches. These results indicate that the US-propelled nanomotors may act as a powerful vehicle for cytosolic delivery of active therapeutic proteins, which would offer an attractive means to enhance the current landscape of intracellular protein delivery and therapy. While CASP-3 is selected as a model protein in this study, the same nanomotor approach can be readily applied to a variety of different therapeutic proteins.