Cancer remains a leading global health challenge, with conventional treatments facing limitations due to drug resistance and adverse effects arising from tumor heterogeneity. Nanozymes, nanomaterials mimicking natural enzymes, have emerged as promising therapeutic agents owing to their catalytic efficiency, stability, and biocompatibility. Among nanozymes, MOFs-based nanozymes are particularly attractive due to the inherent tunability of MOFs, which allows for precise control over their structure, porosity, and catalytic activity. This review comprehensively explores the recent advancements in optimizing cancer therapy through MOFs-based nanozymes. We delve into the classification of these nanozymes based on their enzyme-mimicking activities, including peroxidase, oxidase, catalase, and superoxide dismutase, and discuss their underlying catalytic mechanisms. Additionally, emerging single-atom nanozymes are discussed as a distinct category. Furthermore, we highlight the diverse therapeutic strategies employing MOFs-based nanozymes, such as starvation therapy, oxygen supply, catalytic therapy, glutathione depletion, and activation of therapeutic agents within tumor microenvironment. By exploiting the unique properties of MOFs, these nanozymes demonstrate enhanced therapeutic efficacy in various cancer treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, and sonodynamic therapy. This review underscores the significant potential of MOFs-based nanozymes as a versatile platform for developing next-generation cancer therapeutics, offering improved targeting, reduced systemic toxicity, and enhanced treatment outcomes.

A discrete platinum(II)-metallacycle was designed using perylene bisimide fluorophore (PPy) and 90° Pt(II) (Pt) units as key components, synthesized through a "coordination-driven self-assembly" approach, which can be applied in imaging-guided synergistic cancer photothermal-chemotherapy.

Cancer immunotherapy holds significant promise for improving cancer treatment efficacy; however, the low response rate remains a considerable challenge. To overcome this limitation, advanced catalytic materials offer potential in augmenting catalytic immunotherapy by modulating the immunosuppressive tumor microenvironment (TME) through precise biochemical reactions. Achieving optimal targeting precision and therapeutic efficacy necessitates a thorough understanding of the properties and underlying mechanisms of tumor-targeted catalytic materials. This review provides a comprehensive and systematic overview of recent advancements in tumor-targeted catalytic materials and their critical role in enhancing catalytic immunotherapy. It highlights the types of catalytic reactions, the construction strategies of catalytic materials, and their fundamental mechanisms for tumor targeting, including passive, bioactive, stimuli-responsive, and biomimetic targeting approaches. Furthermore, this review outlines various tumor-specific targeting strategies, encompassing tumor tissue, tumor cell, exogenous stimuli-responsive, TME-responsive, and cellular TME targeting strategies. Finally, the discussion addresses the challenges and future perspectives for transitioning catalytic materials into clinical applications, offering insights that pave the way for next-generation cancer therapies and provide substantial benefits to patients in clinical settings.

Metabolic processes in living organisms depend on the synergistic actions of enzymes working in proximity and in concert, catalyzing reactions effectively while regulating the formation of metabolites. This enzyme synergy offers promising therapeutic application for diseases such as alcohol intoxication, cancer, and hyperinflammation. Despite their potential, the clinical translation of enzyme cascades is restricted by challenges including poor enzyme stability, short half-life, and a lack of delivery strategies that maintain enzyme proximity. In this study, multi-enzyme nanocascades synthesized are developed through in situ atom transfer radical polymerization using a zwitterionic monomer. This method markedly enhances enzyme stability and proximity, thereby prolonging their circulation half-life after systemic administration. It is demonstrated that the nanocascades of uricase and catalase effectively reduce uric acid levels without excessive hydrogen peroxide production, providing a potential antidote for hyperuricemia. Moreover, in a murine breast cancer model, the nanocascades of glucose oxidase and catalase inhibited tumor progression and enhanced the therapeutic efficacy of doxorubicin. The prolonged circulation and promoted reaction efficacy of these nanocascades underscore their substantial potential in enzyme replacement therapy and the treatment of various diseases.

Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with "cold" and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.

The tumor microenvironment (TME) is characterized by hypoxia and low immunogenicity, with a dense and rigid extracellular matrix (ECM) that impedes the diffusion of therapeutic agents and immune cells, thereby limiting the efficacy of immunotherapy. To overcome these challenges, an oxygen defect piezoelectric-photothermal sensitizer, bismuth vanadate nanorod-supported platinum nanodots (BVP) is developed. The integration of platinum enhances the photothermal effect and improves charge separation efficiency under ultrasound, leading to increased heat generation and the production of reactive oxygen species (ROS) and oxygen. Platinum also catalyzes the conversion of hydrogen peroxide in the TME to oxygen, which serves as both a ROS source and a means to alleviate tumor hypoxia, thereby reversing the immunosuppressive TME. Moreover, the coordination of bismuth ions with glutathione further amplifies cellular oxidative stress. The generated heat and ROS not only denature the collagen in the ECM, facilitating the deeper penetration of BVP into the tumor but also induce immunogenic cell death in tumor cells. Through the "degeneration and penetration" strategy, photoacoustic therapy effectively activates immune cells, inhibiting both tumor growth and metastasis. This study introduces a pioneering approach in the design of antitumor nanomedicines aimed at reversing the immunosuppressive characteristics of the TME.

Aluminum adjuvants (Alum), approved by the US Food and Drug Administration, have been extensively used in vaccines containing recombinant antigens, subunits of pathogens, or toxins for almost a century. While Alums typically elicit strong humoral immune responses, their ability to induce cellular and mucosal immunity is limited. As an alternative, layered double hydroxide (LDH), a widely used antacid, has emerged as a novel class of potent nano-aluminum adjuvants (NanoAlum), demonstrating advantageous physicochemical properties, biocompatibility and adjuvanticity in both humoral and cellular immune responses. In this review, we summarize and compare the advantages and disadvantages of Alum and NanoAlum in these properties and their performance as adjuvants. Moreover, we propose the key features for ideal adjuvants and demonstrate that LDH NanoAlum is a promising candidate by summarizing its current progress in immunotherapeutic cancer treatments. Finally, we conclude the review by offering our integrated perspectives about the remaining challenges and future directions for NanoAlum's application in preclinical/clinical settings.

Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug-based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus-responsive CPT nano-prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus-responsive CPT nano-prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus-responsive CPT nano-prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano-prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected.

With large specific surface area, controllable pore size, increased active sites, and structural stability, two-dimensional metal organic frameworks (2D MOFs) have emerged as promising nanomedicines in cancer therapy. These distinctive features make 2D MOFs particularly advantageous in cancer treatment and the corresponding application has gained considerable popularity, signifying significant application potential. Herein, recent advances in various applications including drug delivery and chemotherapy, photodynamic therapy, sonodynamic therapy, chemodynamic therapy, catalytic therapy, and combined therapy were summarized, with emphasis on the latest progress of new materials and mechanisms for these processes. Moreover, the current challenges, potential solutions, and possible future directions are discussed as well.

The cancer therapeutic efficacy of the peroxidase (POD)-mimicking nanozyme-based monotherapy is significantly hindered due to insufficient intratumoral hydrogen peroxide (H2O2) and glutathione (GSH) consumption effect on reactive oxygen species (ROS). In this study, we present the development of poly(o-phenylenediamine)@gold nanoparticles (AuNPs) (PoPD@Au) nanocomposites for multifunctional catalytic-photothermal therapy. These nanocomposites exhibit triple distinct nanozymatic activities, i.e., POD-like activity that catalyzes H2O2 to ROS, glucose oxidase (GOx)-like activity that supplements endogenous H2O2, and GSH depleting activity that decreases the ROS consumption efficiency. This open source and reduce expenditure strategy for ROS generation allows for the amplification of tumor oxidative stress, thereby enhancing anti-tumor efficiency. Additionally, the PoPD@Au nanocomposites demonstrate outstanding photothermal conversion efficiency, contributing to the synergistic effect between PoPD and AuNPs. Moreover, we reveal the improved photothermal performance of PoPD@Au triggered by the tumor microenvironment pH, which provides additional benefits for targeted catalytic-photothermal therapy. This "four-in-one" design of PoPD@Au enables efficient anti-tumor effects both in vitro and in vivo, making it a universal strategy for engineering catalytic-photothermal therapeutic nanoagents.

The unique physicochemical properties inherent to nanoscale materials have unveiled numerous potential applications, spanning beyond the pharmaceutical and medical sectors into various consumer industries like food and cosmetics. Consequently, humans encounter nanomaterials through diverse exposure routes, giving rise to potential health considerations. Noteworthy among these materials are silica and specific metallic nanoparticles, extensively utilized in consumer products, which have garnered substantial attention due to their propensity to accumulate and induce adverse effects in the liver. This review paper aims to provide an exhaustive examination of the molecular mechanisms underpinning nanomaterial-induced hepatotoxicity, drawing insights from both in vitro and in vivo studies. Primarily, the most frequently observed manifestations of toxicity following the exposure of cells or animal models to various nanomaterials involve the initiation of oxidative stress and inflammation. Additionally, we delve into the existing in vitro models employed for evaluating the hepatotoxic effects of nanomaterials, emphasizing the persistent endeavors to advance and bolster the reliability of these models for nanotoxicology research.

Given the crucial role of immune system in the occurrence and progression of various diseases such as cancer, wound healing, bone defect, and inflammation-related diseases, immunomodulation is recognized as a potential solution for treatment of these diseases. Immunomodulation includes both immunosuppression in hyperactive immune conditions and immune activation in hypoactive conditions. For these purposes, metal-organic frameworks (MOFs) are investigated to modulate immune responses either by their own bioactivities or by delivering immunomodulatory agents due to their excellent biodegradability and high delivery capacity. This review starts with an overview of the synthesis strategies of immunomodulatory MOFs, followed by a summarization on the latest applications of immunomodulatory MOFs in cancer immunomodulatory, wound healing, inflammatory disease, and bone tissue engineering. A variety of design considerations, in order to optimize immunomodulatory properties and efficacy of MOFs, is also involved. Last, the challenges and perspectives of future research, which are expected to provide researchers with new insight into the design and application of immunomodulatory MOFs, are discussed.

3D printing is now recognized as a significant tool for medical research and clinical practice, leading to the emergence of medical 3D printing technology. It is essential to improve the properties of 3D-printed products to meet the demand for medical use. The core of generating qualified 3D printing products is to develop advanced materials and processes. Taking advantage of nanomaterials with tunable and distinct physical, chemical, and biological properties, integrating nanotechnology into 3D printing creates new opportunities for advancing medical 3D printing field. Recently, some attempts are made to improve medical 3D printing through nanotechnology, providing new insights into developing advanced medical 3D printing technology. With high-resolution 3D printing technology, nano-structures can be directly fabricated for medical applications. Incorporating nanomaterials into the 3D printing material system can improve the properties of the 3D-printed medical products. At the same time, nanomaterials can be used to expand novel medical 3D printing technologies. This review introduced the strategies and progresses of improving medical 3D printing through nanotechnology and discussed challenges in clinical translation.

Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents can induce pyroptosis via caspase-3 activation. However, these agents also enhance cyclooxygenase-2 (COX-2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy-induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT-Pt-In) containing both indomethacin (In, a COX-2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self-assemble into nanoparticles (denoted as Pt-In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX-2 expression, hence overcoming the chemoresistance and amplifying cisplatin-induced pyroptosis. In a pancreatic cancer mouse model, Pt-In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti-programmed death ligand (α-PD-L1) treatment, Pt-In NP demonstrate the ability to completely suppress metastatic tumors, transforming "cold tumors" into "hot tumors". Overall, the sustained release of Pt(IV) and In from Pt-In NP amplifies platinum-drug-induced pyroptosis to elicit long-term immune responses, hence presenting a generalizable strategy for pancreatic cancer.

Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO3 NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO3 NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O2. The released Ca2+ led to Ca2+ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO3 NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO3 NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.

The weak catalytic activity of nanocatalysts and the insufficient endogenous hydrogen peroxide (H2O2) in tumor microenvironment (TME) seriously restricted the efficacy of catalytic therapy, and the non-degradability of inorganic nanocarriers was also unfavorable for their clinical applications. Herein, by depositing gold nanoparticles (AuNPs) and platinum nanoparticles (PtNPs) with ultrasmall size and modifying photosensitizer (IR808), a biocompatible bovine serum albumin (BSA) nanoplatform (BSA@Au/Pt-IR808) with triple-amplification of enzyme activity was constructed to enhance photodynamic therapy (PDT) and catalytic therapy. Ultrasmall AuNPs possessed glucose oxidase (GOx)-like activity, by which the self-supplying H2O2 accelerated the dual-enzyme activity of peroxidase (POD) and catalase (CAT) of ultrasmall PtNPs, promoting the generation of hydroxyl radical (·OH) and singlet oxygen (1O2). Compared with BSA-IR808 and BSA@Pt, the yields of 1O2 and ·OH of BSA@Au/Pt-IR808 increased by 38.2% and 18.6%. Under the combination action of photothermal therapy (PTT)/PDT/catalytic therapy of BSA@Au/Pt-IR808, the cell viability significantly reduced to 12.8%, and the tumors were completely eliminated, demonstrating the enhanced PDT and catalytic therapy against breast cancer.

The discovery of regulated cell death (RCD) revolutionized chemotherapy. With caspase-dependent apoptosis initially being thought to be the only form of RCD, many drug development strategies aimed to synthesize compounds that turn on this kind of cell death. While yielding a variety of drugs, this approach is limited, given the acquired resistance of cancers to these drugs and the lack of specificity of the drugs for targeting cancer cells alone. The discovery of non-apoptotic forms of RCD is leading to new avenues for drug design. Evidence shows that ferroptosis, a relatively recently discovered iron-based cell death pathway, has therapeutic potential for anticancer application. Recent studies point to the interrelationship between iron and other essential metals, copper and zinc, and the disturbance of their respective homeostasis as critical to the onset of ferroptosis. Other studies reveal that several coordination complexes of non-iron metals have the capacity to induce ferroptosis. This collective knowledge will be assessed to determine how chelation approaches and coordination chemistry can be engineered to program ferroptosis in chemotherapy.

Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

Chemodynamic therapy (CDT) based on Fenton/Fenton-like reaction has emerged as a promising cancer treatment strategy. Yet, the strong anti-oxidation property of tumor microenvironment (TME) caused by endogenous glutathione (GSH) still severely impedes the effectiveness of CDT. Traditional CDT nanoplatforms based on core@shell structure possess inherent interference of different subunits, thus hindering the overall therapeutic efficiency. Consequently, it is urgent to construct a novel structure with isolated functional units and GSH depletion capability to achieve desirable combined CDT therapeutic efficiency.

Herein, a surface curvature-induced oriented assembly strategy is proposed to synthesize a sushi-like novel Janus therapeutic nanoplatform which is composed of two functional units, a FeOOH nanospindle serving as CDT subunit and a mSiO2 nanorod serving as drug-loading subunit. The FeOOH CDT subunit is half covered by mSiO2 nanorod along its long axis, forming sushi-like structure. The FeOOH nanospindle is about 400 nm in length and 50 nm in diameter, and the mSiO2 nanorod is about 550 nm in length and 100 nm in diameter. The length and diameter of mSiO2 subunit can be tuned in a wide range while maintaining the sushi-like Janus structure, which is attributed to a Gibbs-free-energy-dominating surface curvature-induced oriented assembly process. In this Janus therapeutic nanoplatform, Fe3+ of FeOOH is firstly reduced to Fe2+ by endogenous GSH, the as-generated Fe2+ then effectively catalyzes overexpressed H2O2 in TME into highly lethal ·OH to achieve efficient CDT. The doxorubicin (DOX) loaded in the mSiO2 subunit can be released to achieve combined chemotherapy. Taking advantage of Fe3+-related GSH depletion, Fe2+-related enhanced ·OH generation, and DOX-induced chemotherapy, the as-synthesized nanoplatform possesses excellent therapeutic efficiency, in vitro eliminating efficiency of tumor cells is as high as ~ 87%. In vivo experiments also show the efficient inhibition of tumor, verifying the synthesized sushi-like Janus nanoparticles as a promising therapeutic nanoplatform.

In general, our work provides a successful paradigm of constructing novel therapeutic nanoplatform to achieve efficient tumor inhibition.

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.

A new kind of negatively charged polymer-shielded supramolecular nano-micelles with dual-responsive property was designed for tumor treatment, which was prepared on the basis of adamantane terminated linear PAsp(DIP) and disulfide-β-cyclodextrin-terminated PAsp(EDA). The supramolecular nano-micelles comprised a 2,3-dimethylmaleic anhydride (DA) protective layer to stabilize the micelles, a pH-responsive core to package hydrophobic model drugs, and a disulfide-crosslinked interlayer to shackle the core against drug leakage under normal physiological conditions. After arriving at the tumor tissue via EPR, the targeting function could be turned on by dislodging DA groups on the surface of micelles, which allowed the drug-loaded nano-micelles to be easily phagocytized by the tumor cells, and then release the drug inside the cells induced by the increased glutathione level and acidic pH. The results indicated that the charge-conversional dual-responsive supramolecular nano-micelles showed excellent antitumor activity.

Over the past decade, iron (Fe)-based hollow nanoplatforms (Fe-HNPs) have attracted increasing attention for cancer theranostics, due to their high safety and superior diagnostic/therapeutic features. Specifically, Fe-involved components can serve as magnetic resonance imaging (MRI) contrast agents (CAs) and Fenton-like/photothermal/magnetic hyperthermia (MTH) therapy agents, while the cavities are able to load various small molecules (e.g., fluorescent dyes, chemotherapeutic drugs, photosensitizers, etc.) to allow multifunctional all-in-one theranostics. In this review, the recent advances of Fe-HNPs for cancer imaging and treatment are summarized. Firstly, the use of Fe-HNPs in single T1-weighted MRI and T2-weighted MRI, T1-/T2-weighted dual-modal MRI as well as other dual-modal imaging modalities are presented. Secondly, diverse Fe-HNPs, including hollow iron oxide (IO) nanoparticles (NPs), hollow matrix-supported IO NPs, hollow Fe-complex NPs and hollow Prussian blue (PB) NPs are described for MRI-guided therapies. Lastly, the potential clinical obstacles and implications for future research of these hollow Fe-based nanotheranostics are discussed.

Covalent organic frameworks (COFs) are a class of organic crystalline porous materials discovered in the early 21st century that have become an attractive class of emerging materials due to their high crystallinity, intrinsic porosity, structural regularity, diverse functionality, design flexibility, and outstanding stability. However, many chemical and physical properties strongly depend on the presence of metal ions in materials for advanced applications, but metal-free COFs do not have these properties and are therefore excluded from such applications. Metalated COFs formed by combining COFs with metal ions, while retaining the advantages of COFs, have additional intriguing properties and applications, and have attracted considerable attention over the past decade. This review presents all aspects of metalated COFs, from synthetic strategies to various applications, in the hope of promoting the continued development of this young field.

Sonosensitizer-mediated sonodynamic therapy (SDT) has emerged as a promising anti-tumor strategy. However, this strategy of continuous oxygen consumption further exacerbates the hypoxic tumor microenvironment, which limits its therapeutic efficacy. In this study, we designed a multifunctional hydrogel (PB+Ce6@Hy) that simultaneously co-delivers nanozyme prussian blue (PB) and sonosensitizer chlorin e6 (Ce6) for the realization of photothermal therapy (PTT) and enhanced SDT. When the hydrogel reaches the tumor tissue through local injection, the 808 nm laser can induce the hydrogel to warm up and soften, thereby triggering the release of PB and Ce6. PB can interact with endogenous H2O2 in situ and generate sufficient oxygen to promote the Ce6-mediated SDT effect. Besides, due to the good encapsulation ability of the hydrogel, the nanomaterials can be released in a controlled manner by changing laser parameter, irradiation time, etc. The experimental results show that the PB+Ce6@Hy system we developed can generate a large amount of reactive oxygen species (ROS), which can be combined with the photothermal effect to kill tumor cells, as a result, tumor proliferation has been adequately inhibited. This combined PTT/SDT dynamic strategy provides a new perspective for Ce6-induced cancer therapy, showing great potential for clinical application.

Reactive oxygen species (ROS) damage is a crucial method with which to inhibit tumor cell proliferation; however, tumor cells can reduce ROS damage by modulating multiple repair mechanisms, thus, reducing the efficacy of ROS damage in tumor therapy. In this study, we built an ultrasound-triggered ROS damage nanoamplifier using a synergistic strategy consisting of ROS damage and decreased tumor self-protection capability to enhance the treatment efficacy of mutant p53 tumors. A ROS damage nanoamplifier (PT@PTGA) was fabricated using amphiphilic polyglutamic acid (PTGA) to load with a sonosensitizer (protoporphyrin IX, PpIX) and an MTH1 inhibitor (TH287). Under ultrasonic excitation, PpIX catalyzes oxygen to produce singlet oxygen and release TH287 to inhibit MTH1 activity, thereby causing the accumulation of 8-oxo-dGTP, which enhances DNA damage and further induces cell apoptosis. In addition, TH287 allies with ROS to eliminate the mutated p53 protein in tumor cells, thus reducing the self-protective capacity of tumor cells. As a result, the "internal and external" aspects were combined to enhance sensitization for mutant p53 tumor therapy. The construction of a ROS nanoamplifier not only provides an effective strategy for the treatment of mutant p53 tumors but also supplies an integrated platform for tumor diagnosis and therapy.

The development of two-dimensional (2D) nanomaterials for cancer therapy has attracted increasing attention due to their high specific surface area, unique ultrathin structure, electronic and photonic properties. For biomedical applications, investigations into the family of 2D materials have been sparked by graphene and its derivatives. Many 2D nanomaterials, including layered double hydroxides, transition metal dichalcogenides, nitrides and carbonitrides, black phosphorus nanosheets, and metal-organic framework nanosheets, are extensively explored as cancer theranostic platforms. In addition to the high drug loading, 2D nanomaterials are featured with improved physiological properties of drugs, prolonged blood circulation, and increased tumor accumulation and bioavailability. As a consequence, 2D nanomaterials have been widely examined in pre-clinical tumor therapy, particularly through the tumor microenvironment (TME) modulation. This review summarizes recent progresses in developing 2D nanomaterials for TME modulating-based cancer diagnosis and therapy. It is anticipated that this review will benefit researchers to obtain a deeper understanding of interactions between 2D nanomaterials and TME components and develop rational and reliable 2D nanomedicines for pre/clinical cancer theranostics.

To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.

Radiotherapy (RT) has been viewed as one of the most effective and extensively applied curatives in clinical cancer therapy. However, the radioresistance of tumor severely discounts the radiotherapy outcomes. Here, an innovative supramolecular radiotherapy strategy, based on the complexation of a hypoxia-responsive macrocycle with small-molecule radiosensitizer, is reported. To exemplify this tactic, a carboxylated azocalix[4]arene (CAC4A) is devised as molecular container to quantitatively package tumor sensitizer banoxantrone dihydrochloride (AQ4N) through reversible host-guest interaction. Benefited from the selective reduction of azo functional groups under hypoxic microenvironment, the supramolecular prodrug CAC4A•AQ4N exhibits high tumor accumulation and efficient cellular internalization, thereby significantly amplifying radiation-mediated tumor destruction without appreciable systemic toxicity. More importantly, this supramolecular radiotherapy strategy achieves an ultrahigh sensitizer enhancement ratio (SER) value of 2.349, which is the supreme among currently reported noncovalent-based radiosensitization approach. Further development by applying different radiosensitizing drugs can make this supramolecular strategy become a general platform for boosting therapeutic effect in cancer radiotherapies, tremendously promising for clinical translation.

Spatiotemporal regulation of multi-enzyme catalysis with stimuli is crucial in nature to meet different metabolic requirements but presents a challenge in artificial cascade systems. Here, we report a strategy for precise and tunable modulation of enzyme-nanozyme cascade reaction kinetics by remote magnetic stimulation. As a proof of concept, glucose oxidase (GOx) was immobilized onto a ferrimagnetic vortex iron oxide nanoring (Fe3O4 NR) functionalized with poly(ethylene glycol) of different molecular weights to construct a series of Fe3O4 NR@GOx with nanometer linking distances. The activities of GOx and the Fe3O4 NR nanozyme in these systems were shown to be differentially stimulated by Fe3O4 NR-mediated local heat in response to an alternating magnetic field (AMF), leading to modulated cascade reaction kinetics in a distance-dependent manner. Compared to the free GOx and Fe3O4 NR mixture, Fe3O4 NR(D2)@GOx with an optimum linking distance of 1 nm exhibits a superior kinetic match between GOx and the Fe3O4 NR nanozyme and over a 400-fold higher cascade activity under AMF exposure. This enables remarkable intracellular reactive oxygen species production and significantly improved tumor inhibition of AMF-stimulated Fe3O4 NR(D2)@GOx in 4T1 tumor-bearing mice. The strategy reported here offers a straightforward new tool for fine-tuning multi-enzyme catalysis at the molecular level using magnetic stimuli and holds great promise for use in a variety of biotechnology and synthetic biology applications.