A mitochondria-targeted anticancer nanoplatform with deep penetration for enhanced synergistic sonodynamic and starvation therapy

Sonodynamic therapy (SDT), as an emerging technique, gives rise to reactive oxygen species (ROS)-induced apoptosis of tumor cells. However, nonselective enrichment and unsatisfactory penetration depth of sonosensitizers in tumor tissues limit its application. In this study, we synthesized core/shell (glucose oxidase (GOx) in the core/hematoporphyrin monomethyl ether (HMME) and IR780 in the shell) structured polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) with deep tumor penetration and mitochondrial targeting capability for synergistic sonodynamic and starvation therapy. After passing through the endothelial space of tumor vasculatures, by virtue of IR780, these NPs can selectively accumulate towards cancer cells/sites, especially in mitochondria and diffuse into deep tumour centres. Upon ultrasound (US) exposure, the overproduced ROS cause tumor cell apoptosis. Sonodynamic effects can be amplified by mitochondrial targeting because mitochondria are susceptible to ROS. GOx blocks glucose (energy) supply, further suppressing the growth of malignant tumors. This synergistic therapy exhibited a superb response to treatment (4.7-fold lower tumor growth in volume than the control group). In addition, these NPs also serve as excellent photoacoustic (PA)/fluorescent (FL) imaging contrast agents to simultaneously monitor and guide cancer therapy. This study paves a promising way to achieve an ideal strategy for cancer therapy.