Defect Engineering Triggers Exceptional Sonodynamic Activity of Manganese Oxide Nanoparticles for Cancer Therapy

Sonodynamic therapy (SDT) has received increasing interest in cancer treatment, but its clinical application is still constrained by the low activity of sonosensitizers and their unclear mechanism. Herein, a kind of oxygen-deficient manganese oxide (MnO_x) nanoparticles with greatly enhanced sonodynamic activity and good biocompatibility is developed as an advanced sonosensitizer. The introduced oxygen defects can remarkably enhance the electrical conductivity of manganese oxide (MnO) nanoparticles and serve as charge trapping sites to prohibit the electron-hole pair recombination upon ultrasound (US) irradiation. Such distinct merits promote the generation of reactive oxygen species (ROS), making MnO_x as a decent sonosensitizer for SDT, and thus endowing MnO_x with higher ROS production under US irradiation. As a demonstration, the MnO_x nanoparticles decorated by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (MnO_x-DSPE-PEG), a biocompatible coverage to enhance the dispersion ability, achieve a superior tumor killing efficiency of 96%, substantially higher than the MnO-DSPE-PEG counterpart (9%). Our experimental results also reveal that MnO_x-DSPE-PEG nanoparticles induce the death of tumor cells by targeting polyunsaturated fatty acids in their membrane with US-triggered ROS. Furthermore, the as-designed sonosensitizers exhibit negligible toxicity toward the treated mice.