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Nanomaterials with more than one enzyme‐like activity are termed multi‐enzymic nanozymes, which have received increasing attention in recent years and hold huge potential to be applied in diverse fields, especially for biosensing and therapeutics. Compared to single enzyme‐like nanozymes, multi‐enzymic nanozymes offer various unique advantages, including synergistic effects, cascaded reactions, and environmentally‐responsive selectivity. Nevertheless, along with these merits, the catalytic mechanism and rational design of multi‐enzymic nanozymes are more complicated and elusive as compared to single‐enzymic nanozymes. In this review, we systematically discussed the multi‐enzymic nanozymes classification scheme based on the numbers/types of activities, the internal and external factors regulating the multi‐enzymatic activities, the rational design based on chemical, biomimetic, and computer‐aided strategies, and recent progress in applications attributed to the advantages of multi‐catalytic activities. Finally, current challenges and future perspectives regarding the development and application of multi‐enzymatic nanozymes are suggested. This review aims to deepen the understanding and inspire the research in multi‐enzymic nanozymes to a greater extent.This article is protected by copyright. All rights reserved

Advances in nanotechnology have enabled the rapid development of stimuli-responsive therapeutic nanomaterials for precision gas therapy. Hydrogen sulfide (H 2 S) is a significant gaseous signaling molecule with intrinsic biochemical properties, which exerts its various physiological effects under both normal and pathological conditions. Various nanomaterials with H 2 S-responsive properties, as new-generation therapeutic agents, are explored to guide therapeutic behaviors in biological milieu. The cross disciplinary of H 2 S is an emerging scientific hotspot that studies the chemical properties, biological mechanisms, and therapeutic effects of H 2 S. This review summarizes the state-of-art research on H 2 S-related nanomedicines. In particular, recent advances in H 2 S therapeutics for cancer, such as H 2 S-mediated gas therapy and H 2 S-related synergistic therapies (combined with chemotherapy, photodynamic therapy, photothermal therapy, and chemodynamic therapy) are highlighted. Versatile imaging techniques for real-time monitoring H 2 S during biological diagnosis are reviewed. Finally, the biosafety issues, current challenges, and potential possibilities in the evolution of H 2 S-based therapy that facilitate clinical translation to patients are discussed.

Mild photothermal therapy (PTT, <45 °C) can prevent tumor metastasis and heat damage to normal tissue, compared with traditional PTT (>50 °C). However, its therapeutic efficacy is limited owing to the hypoxic tumor environment and tumor thermoresistance owing to the overproduction of heat shock proteins (HSPs). Herein, a near‐infrared (NIR)‐triggered theranostic nanoplatform (GA‐PB@MONs@LA) is designed for synergistic mild PTT and enhanced Fenton nanocatalytic therapy against hypoxic tumors. The nanoplatform is fabricated by the confined formation of Prussian blue (PB) nanoparticles in mesoporous organosilica nanoparticles (MONs), followed by the loading of gambogic acid (GA), an HSP90 inhibitor, and coating with thermo‐sensitive lauric acid (LA). Upon NIR irradiation, the photothermal effect (44 °C) of PB not only induces apoptosis of tumor cells but also triggers the on‐demand release of GA, inhibiting the production of HSP90. Moreover, the delivered heat simultaneously enhances the catalase‐like and Fenton activity of PB@MONs@LA in an acidic tumor microenvironment, relieving the tumor hypoxia and promoting the generation of highly toxic •OH. In addition, the nanoplatform enables magnetic resonance/photoacoustic dual‐modal imaging. Thus, this study describes a distinctive paradigm for the development of NIR‐triggered theranostic nanoplatforms for enhanced cancer therapy.

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF 4 :Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO − ). By simply adjusting the Ce 3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO − in the tumor. Obtained ONOO − effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO − , and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO − to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy.

Therapeutic nanosystems triggered by a specific tumor microenvironment (TME) offer excellent safety and selectivity in the treatment of cancer by in situ conversion of a less toxic substance into effective anticarcinogens. However, the inherent antioxidant systems, hypoxic environment, and insufficient hydrogen peroxide (H2O2) in tumor cells severely limit their efficacy. Herein, a new strategy has been developed by loading the chemotherapy prodrug disulfiram (DSF) and coating glucose oxidase (GOD) on the surface of Cu/ZIF-8 nanospheres and finally encapsulating manganese dioxide (MnO2) nanoshells to achieve efficient DSF-based cancer chemotherapy and dual-enhanced chemodynamic therapy (CDT). In an acidic TME, the nanocatalyst can biodegrade rapidly and accelerate the release of internal active substances. The outer layer of MnO2 depletes glutathione (GSH) to destroy the reactive oxygen defensive mechanisms and achieves continuous oxygen generation, thus enhancing the catalytic efficiency of GOD to burst H2O2. Benefiting from the chelation reaction between the released Cu2+ and DSF, a large amount of cytotoxic CuET products is generated, and the Cu+ are concurrently released, thereby achieving efficient chemotherapy and satisfactory CDT efficacy. Furthermore, the release of Mn2+ can initiate magnetic resonance imaging signals for the tracking of the nanocatalyst.

Mitochondria are the "power plant" of the cell, providing a constant source of energy, and are involved in a variety of intracellular signaling pathways. Among these pathways, Ca 2+ homeostasis is closely related to the normal function of mitochondria. By destroying the Ca 2+ steady state of mitochondria and disrupting their multiple cellular activities, tumor cell killing can be achieved. In addition, the presence of an intracellular oxidative stress state triggers the closure of cellular calcium channels, which leads to intracellular Ca 2+ retention and enrichment. We designed a targeted and tumor microenvironment (TME)-responsive CaO 2 -based nanosystem that can selectively target cancer cells for pH-controlled degradation and drug release, alter cellular physiological mechanisms by disrupting Ca 2+ homeostasis in an artificial manner, and introduce mitochondrial Ca 2+ excess-mediated apoptosis. Meanwhile, the production of Ca(OH) 2 will raise the pH of the microenvironment and subsequently promote the oxidation process of glutathione by H 2 O 2 released from CaO 2 degradation, achieving the goal of remodeling TME. Moreover, calcium overload of tumor cells and calcification of tissues can both inhibit tumor growth and act as a contrast agent for computed tomography imaging.