Ultrasound-Responsive Perfluorohexane Nanodroplets for Cell-Targeted Histotripsy and Therapy

Ultrasound-based therapies such as histotripsy and sonodynamic therapy have gained significant attention in recent years for their ability to treat various diseases noninvasively. However, commonly used microbubbles have a limited cell targeting property due to their large size. Here, we report an ultrasound-responsive perfluorohexane nanodroplet that can be used for cell-selective histotripsy and sonodynamic therapy. The amphiphilic polylactide is designed as a stabilizer for 45-85 nm nanodroplets, which are functionalized with affinity biomolecules and loaded with a sonosensitizer (chlorin e6). Nanodroplets are selectively internalized into specific cells and then converted to microbubbles upon ultrasound irradiation. This leads to mechanical stress and cell membrane rupture through histotripsy. In addition, ultrasound exposure generates intracellular reactive oxygen species by the sonosensitizer that further enhances oxidative stress-mediated cell death. Designed nanodroplets offer a promising platform for cell-selective therapy of different diseases.