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

Abstract

normal cells and is more sensitive to reactive oxygen species (ROS) elevation has attracted considerable attention. [1] From this perspective, ROS-generating approaches have been widely explored as a weapon to directly or indirectly kill cancer cells; these include photodynamic therapy (PDT), [2] radiodynamic therapy (RT), [3] sonodynamic therapy (SDT), [4] and chemodynamic therapy (CDT). [5] Promoted by recent advancements in nanochemistry and nanocatalysis, a variety of nanosystems with enzyme-like activities, also called "nanozymes," have been successfully fabricated and applied in various biomedical applications. [6] Among these applications, nanozyme-initiated CDT (NCDT) is emerging as a novel cancer treatment strategy with the potential to mitigate undesired side effects. NCDT is a highly tumor-specific modality for cancer therapy triggered by peroxidase (POD)-like nanozyme-mediated chemical reactions, that is, in situ catalysis of endogenous hydrogen peroxide (H 2 O 2 ) into highly toxic hydroxyl radicals ( • OH) to induce cell apoptosis and necrosis. Although many nanomaterials, including ferromagnetic nanoparticles (γ-Fe 2 O 3 or Fe 3 O 4 ), [7] vanadium oxides, [8] copper oxide, [9] and cerium oxide (CeO 2 ), [10] have revealed POD-like activity for cancer diagnosis Clinical applications of nanozyme-initiated chemodynamic therapy (NCDT) have been severely limited by the poor catalytic efficiency of nanozymes, insufficient endogenous hydrogen peroxide (H 2 O 2 ) content, and its off-target consumption. Herein, the authors developed a hollow mesoporous Mn/Zrco-doped CeO 2 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 H 2 O 2 homeostasis disruptor promotes H 2 O 2 evolution and restrains off-target elimination of H 2 O 2 to achieve intensive NCDT. PHMZCO-AT with SOD-like activity catalyzes endogenous superoxide anion (O 2 •− ) into H 2 O 2 in the tumor region. The suppression of CAT activity and depletion of glutathione by PHMZCO-AT largely weaken the off-target decomposition of H 2 O 2 to H 2 O. Elevated H 2 O 2 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 Mn 2+ 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 H 2 O 2 homeostasis.The ORCID identification number(s) for the author(s) of this article can be found under

Insights on catalytic mechanism of CeO2 as multiple nanozymes

“…The above investigations indicated a correlation between the structural defects of ceria nanozymes and their catalytic activity as peroxidase mimics [31,55,[96][97][98][99][100]. The high catalytic activity was found on the CeO 2 nanozymes featured with the high level of the surface Ce 3+ fraction and large surface area.…”

Antioxidant Therapy in Cancer: Rationale and Progress

“…The SOD family constitutes the first line of defense against ROS. The O 2 •− is dismutated by SODs to form H 2 O 2 , which can be decomposed into O 2 and H 2 O by CAT or GPXs [ 66 ]. Several enzymes, such as glutathione reductase and glucose-6-phosphate dehydrogenase, function as secondary antioxidant enzymes that enable GPX to function with cofactors (NADPH, GSH and glucose 6-phosphate) but not to act on ROS directly [ 67 , 68 ].…”

Manganese-based hollow nanoplatforms for MR imaging-guided cancer therapies

“…Dong et al [ 126 ] reported a hollow mesoporous tandem nanozyme (denoted PHMZCO-AT) for T 1 -weighted MR/CT imaging-guided highly efficient catalytic treatment (Fig. 5 ).…”

“…Reproduced with permission from Ref. [ 126 ]. Copyright 2022, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim …”