Ultrasound-activated Au/ZnO-based Trojan nanogenerators for combined targeted electro-stimulation and enhanced catalytic therapy of tumor

Abstract Integrating the advantages of multiple therapies into one therapeutic platform is highly desired for augmented treatment effects. Herein, by modifying MLS and PEG on ZnO-nanorods/AuNPs nanoassemblies and coating with C6 cell membrane (MP-Au/ZnO@CCM), we construct a novel ultrasound-activatable Au/ZnO-based tumor therapeutic platform (Trojan nanogenerators) and exploit it for effective tumor therapy. The developed MP-Au/ZnO@CCM nanogenerators worked well in multiple ways to achieve targeted electrostimulation and enhanced catalytic therapy of tumor, under ultrasound excitation. Firstly, the ZnO-nanogenerators will generate a piezoelectric potential difference of about 140 mV by ultrasonic excitation when targeted (by MLS moiety) to the mitochondria, disrupting the mitochondrial membrane potential for electrostimulation. Secondly, the nanogenerators enhances greatly multiple enzyme-like activities of Au nano-components for enhanced tumor catalytic therapy. Among them, the affinity and maximum reaction rate of peroxidase-like are increased by 34.99% and 53.36% respectively through kinetic analysis. Simulations and calculations revealed the roles of piezoelectric polarization electric field and displacement current in enhancing catalytic activity. The superior tumor suppressive effect of the MP-Au/ZnO@CCM was confirmed by in-vitro cell study and in-vivo C6 tumor-bearing mouse models. The developed ultrasound-activated nanogenerators will provide a unique electrostimulation tumor therapy strategy and opens a new way for improving the therapeutic efficacy of nanozymes.