As prospective alternatives for natural enzymes, catalytically active nanomaterials, known as "nanozymes" have attracted considerable interest over the past decade owing to their obvious

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

Reducing the scavenging capacity of reactive oxygen species (ROS) and elevating ROS production are two primary goals of developing novel sonosensitizers for sonodynamic therapy (SDT). Hence, ultrathin 2D Bi2MoO6–poly(ethylene glycol) nanoribbons (BMO NRs) are designed as piezoelectric sonosensitizers for glutathione (GSH)‐enhanced SDT. In cancer cells, BMO NRs can consume endogenous GSH to disrupt redox homeostasis, and the GSH‐activated BMO NRs (GBMO) exhibit an oxygen‐deficient structure, which can promote the separation of electron–hole pairs, thereby enhancing the efficiency of ROS production in SDT. The ultrathin GBMO NRs are piezoelectric, in which ultrasonic waves introduce mechanical strain to the nanoribbons, resulting in piezoelectric polarization and band tilting, thus accelerating toxic ROS production. The as‐synthesized BMO NRs enable excellent computed tomography imaging of tumors and significant tumor suppression in vitro and in vivo. A piezoelectric Bi2MoO6 sonosensitizer‐mediated two‐step enhancement SDT process, which is activated by endogenous GSH and amplified by exogenous ultrasound, is proposed. This process not only provides new options for improving SDT but also broadens the application of 2D piezoelectric materials as sonosensitizers in SDT.

The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper­(II)-based tetrakis­(4-carboxy phenyl)­porphyrin (TCPP) nanoscale metal–organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224­(Cu)-GOD@MnO2). The coated MnO2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O2 from H2O2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H2O2 for the subsequent Cu+-based Fenton-like reaction. Meanwhile, the Cu2+ chelated to the TCPP ligand is converted to Cu+ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu+ reacts with the plentiful H2O2 by enzyme catalysis to produce a toxic hydroxyl radical (•OH), and singlet oxygen (1O2) is synchronously generated from combination with Cu+, O2, and H2O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn2+-induced T 1-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224­(Cu)-GOD@MnO2 nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.

A NO-release platform based on upconversion dendritic mesoporous silica nanocomposites was invented for combined imaging-guided synergistic chemodynamic/photodynamic/gas therapy.

Tailored to the peculiar tumor microenvironment, Fenton reaction-based chemodynamic therapy (CDT) has attracted considerable attention for tumor treatment. However, the efficacy of CDT is highly limited by both H 2 O 2 overproduction and the low activity of catalysts at the tumor site. Herein, a novel magnetic targeting nanoplatform (γ-Fe 2 O 3 -GOx-DMSN) has been designed by simply depositing ultrasmall γ-Fe 2 O 3 nanoparticles and natural glucose oxidase (GOx) into the large mesopores (∼13 nm) of dendritic mesoporous silica (DMSN) spheres for near-infrared (NIR) light-enhanced CDT efficacy. In this structure, GOx can effectively consume glucose in the tumor cells to induce a decrease in the pH value and generate a considerable amount of H 2 O 2 , both of which promote subsequent Fenton reaction. These ultrasmall γ-Fe 2 O 3 nanoparticles not only serve as an efficacious Fenton catalyst for degradation of the increased H 2 O 2 within the tumor to produce highly toxic hydroxyl radicals ( • OH) but also exhibit high photothermal therapy (PTT) efficiency upon irradiation with 808 nm light. Importantly, the generated hypothermia can significantly accelerate the Fenton process, thereby enabling a synergetic PTT/hypothermia-enhanced CDT effect. Our work manifests a proof of concept of H 2 O 2 -evolving and NIR-enhanced CDT, providing a new perspective for cancer therapy.

The development of the advanced imaging probe holds the key to the achievement of target imaging and metastasis tracing. The bismuth based nanoprobe has been regarded as the most promising X-ray computed tomography probe due to its largest X-ray attenuation coefficient. Accordingly, the bismuth nanoparticles with controllable size distribution and light weight have been fabricated through a one pot synthesis strategy. The surface modification can be easily conducted with the polyethylene glycol to make the nanoparticles hydrosoluble and biocompatible. More importantly, the Bi nanoparticles can be excited by light to conduct excitation wavelength dependent emission in the visible (Vis) and near-infrared (NIR) region, which makes it possible to utilize it for fluorescence imaging. Under the detection of the multimode CT/fluorescence imaging, the long circulation time of the Bi nanoparticles and its specific accumulation at the liver and intestine can be visually displayed. The facile and large scale preparation method, unique luminescence property, and multimode imaging function endow the Bi nanoparticles with promising applications in clinical diagnosis.

Arming activatable mild-photothermal therapy (PTT) with the property of relieving tumor thermotolerance holds great promise for overcoming traditional mild PTT limitations such as thermoresistance, insufficient therapeutic effect, and off-target heating. Herein, a mitochondria-targeting, defect-engineered AFCT nanozyme with enhanced multi-enzymatic activity was elaborately designed as a tumor microenvironment (TME)-activatable phototheranostic agent to achieve remarkable anti-tumor therapy via “electron transport chain (ETC) interference and synergistic adjuvant therapy”. Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the AFCT nanozymes with excellent catalytic activity. In TME, open sources of H2O2 can be achieved by superoxide dismutase-mimicking AFCT nanozymes. In response to the dual stimuli of H2O2 and mild acidity, the peroxidase-mimicking activity of AFCT nanozymes not only catalyzes the accumulation of H2O2 to generate ·OH but also converts the loaded 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form with strong near-infrared absorption, specifically unlocking its photothermal and photoacoustic imaging properties. Intriguingly, the undesired thermoresistance of tumor cells can be greatly alleviated owing to the reduced expression of heat shock proteins enabled by NADH POD-mimicking AFCT-mediated NADH depletion and consequent restriction of ATP supply. Meanwhile, the accumulated ·OH can facilitate both apoptosis and ferroptosis in tumor cells, resulting in synergistic therapeutic outcomes in combination with TME-activated mild PTT.