Targeted self-activating Au-Fe3O4 composite nanocatalyst for enhanced precise hepatocellular carcinoma therapy via dual nanozyme-catalyzed cascade reactions

Abstract Catalytic nanozyme-based tumor therapy is currently considered as a promising strategy in anti-tumor treatment, but it also has some disadvantages such as systemic toxicity, off-target, and non-specificity, leading to lowered therapeutic precision and efficacy in clinical curability. To overcome these limitations, herein we report a distinct strategy of nanocatalytic tumor precision therapy via tumor cell-specific CD44 targeted nanozyme-catalyzed cascade reactions. Briefly, the composite nanozyme CD44MMSN/AuNPs were assembled with two self-activable nanocatalysts including the inner core peroxidase-mimic Fe3O4 magnetic nanoparticles (MNPs), and the outer glucose oxidase-mimic AuNPs situated within large aperture mesoporous silicon (MMSN/AuNPs), and then functionalized with cell ligand hyaluronic acid (HA), which can specifically target transmembrane CD44 receptor of HepG2 tumor cells. In terms of catalysis, we found the coupled AuNPs effectively catalyzed glucose to produce H2O2, which was inversely catalyzed by Fe3O4 NPs and AuNPs to produce more hydroxyl radicals (•OH) in tumor microenvironment (TME). That is, this composite nanozyme performed self-activable reactive oxygen species (ROS)-mediated cascade reactions, and thereby resulted in significantly specific growth inhibition of hepatocellular carcinoma HepG2 cells. The present results also showed that the composite nanozyme CD44MMSN/AuNPs could specifically induce a greater number of HepG2 cell apoptosis and death. More importantly, we elucidated the mechanism of the composite nanozyme CD44MMSN/AuNPs via inducing HepG2 cell apoptosis and death from subcellular level. Therefore, this study represents an insightful paradigm for achieving nanocatalytic tumor precision therapy through rationally designing tumor cell-targeting inorganic nanozyme with self-activable cascade reactions.