Engineered Extracellular Vesicles for Safe and Efficient Chemo-Sonodynamic Cancer Therapy via Stimuli-Responsive Drug Release

Sonodynamic therapy (SDT) is a novel non-invasive cancer treatment that utilizes ultrasound to activate sonosensitizers and generate reactive oxygen species (ROS) to damage tumor cells. Nanocarriers-assisted delivery of sonosensitizers has gained considerable attention because it can significantly improve the physicochemical properties and anticancer activities of sonosensitizers. Extracellular vesicles (EVs), a class of naturally occurring nanoparticles secreted by cells, were extensively employed as biocompatible nanocarriers for drug delivery as an alternative to synthetic nanocarriers. Combination of SDT with chemotherapy has shown great promise to achieve synergistic therapeutic outcomes for cancer treatment. In this study, stimuli-responsive EVs that can selectively release chemotherapeutic agents and sonosensitizers into cancer cells were developed for safe and efficient chemo-sonodynamic cancer therapy. The engineered stimuli-responsive EVs facilitated the release of chemodrugs and sonosensitizers in response to acidic pH in the endo/lysosomes or redox potentials in the cytoplasm. <i>In vivo </i>studies using tumor-bearing mouse models demonstrated that the stimuli-responsive EVs preferential accumulated in tumors and exhibited efficient anticancer activity without significant systemic toxicity. These findings demonstrate that stimuli-responsive EVs are promising platforms for safe and efficient chemo-sonodynamic combination cancer therapy.