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

This review aims to summarize the latest knowledge on factors, diagnosis, and treatment of pancreatic cancer, and aims to promote further research on this under-studied malignant tumor. At present, we urgently need to identify high-risk patients with precancerous diseases through screening approaches, so that medical professionals and the general public may better understand prevention strategies or early detection measures. Pancreatic cancer is a highly invasive malignant tumor with a fatal risk, mainly seen in men and older adults (60-85 years old). Pancreatic cancer is now increasingly observed in young patients. Because the disease has no early symptoms and can quickly invade surrounding tissues and organs, it is one of the deadliest cancers. With a view to identify the important factors for the development of pancreatic cancer, previous studies have found that smoking, alcohol, and chronic pancreatitis are considered high-risk factors. Recent studies have shown that abnormal metabolism of human microorganisms, blood type, and glucose and lipid levels are also important factors in the development of pancreatic cancer. Identifying early diagnosis options is an important way to improve detection and survival rates of pancreatic cancer. None of the many tumor markers associated with pancreatic cancer are highly specific, which also indicates further research is required to improve the early detection rate. Future directions in terms of treatment evaluating the relationship between the microbiology-free system and immunotherapy will bring a major breakthrough and is expected to bring exciting clinical applications in improving the life-cycle of pancreatic cancer patients.

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.

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state in the tumor microenvironment (TME), the therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB therapy to kill tumors efficiently. The tumor cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnO x ) nanozyme termed CM@Mn showed intrinsic peroxidase and oxidase-like activities in an acidic TME. These activities can generate toxic hydroxyl (•OH) and superoxide radicals (•O2 –) for tumor cell killing and evoking immunogenic cell death (ICD). Furthermore, the TME-responsive release of Mn2+ directly promotes dendritic cell maturation and macrophage M1 repolarization, resulting in the reversal of an immunosuppressive TME into an immune-activating environment. Additionally, tumor hypoxia relief caused by catalase-like activity also contributes to the process of TME reversal. Finally, a robust tumor-specific T cell-mediated antitumor response occurs with the support of the PD-1 checkpoint blockade. The proliferation of primary and metastatic tumors was inhibited, and a long-term immune memory effect was induced. The therapeutic strategy outlined here may serve as a promising candidate for tumor-integrated treatment.

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