Guiding Transition Metal-Doped Hollow Cerium Tandem Nanozymes with Elaborately Regulated Multi-Enzymatic Activities for Intensive Chemodynamic Therapy

Clinical applications of nanozyme-initiated chemodynamic therapy (NCDT) have been severely limited by the poor catalytic efficiency of nanozymes, insufficient endogenous hydrogen peroxide (H2O2) content, and its off-target consumption. Herein, the authors developed a hollow mesoporous Mn/Zr-co-doped CeO2 tandem nanozyme (PHMZCO-AT) with regulated multi-enzymatic activities, that is, the enhancement of superoxide dismutase (SOD)-like and peroxidase (POD)-like activities and inhibition of catalase (CAT)-like activity. PHMZCO-AT as a H2O2 homeostasis disruptor promotes H2O2 evolution and restrains off-target elimination of H2O2 to achieve intensive NCDT. PHMZCO-AT with SOD-like activity catalyzes endogenous superoxide anion (O-2(center dot-)) into H2O2 in the tumor region. The suppression of CAT activity and depletion of glutathione by PHMZCO-AT largely weaken the off-target decomposition of H2O2 to H2O. Elevated H2O2 is then catalyzed by the downstream POD-like activity of PHMZCO-AT to generate toxic hydroxyl radicals, further inducing tumor apoptosis and death. T-1-weighted magnetic resonance imaging and X-ray computed tomography imaging are also achieved using PHMZCO-AT due to the existence of paramagnetic Mn2+ and the high X-ray attenuation ability of elemental Zr, permitting in vivo tracking of the therapeutic process. This work presents a typical paradigm to achieve intensive NCDT efficacy by regulating multi-enzymatic activities of nanozymes to perturb the H2O2 homeostasis.