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Covalent organic frameworks (COFs) are a class of porous crystalline materials with exceptional properties, constructed through covalently linked organic units. COFs are extensively applied in the field of biomedicine, particularly in the context of anticancer treatments. First, this review summarizes the diverse synthetic methods of COFs, including solvothermal synthesis, microwave‐assisted synthesis, room temperature synthesis, interface synthesis, ionothermal techniques, mechanical grinding, and electrochemical methods, and their impacts on the material's structure and performance. Second, COFs exhibit tremendous potential in the field of cancer therapy because of their orderly lattice structure, tunable pore sizes, high surface area, and excellent thermal and chemical stability. Therefore, the article deeply explores the applications of COFs in diverse cancer treatment modalities, encompassing early diagnostic bioimaging, drug delivery, various phototherapies, chemodynamic therapy, sonodynamic therapy, radiation therapy, and their combined therapeutic strategies. Finally, the article points out current research challenges and future directions in this field.

To realize precise tumor treatment, chemodynamic therapy (CDT) that utilizes metal element to trigger Fenton or Fenton‐like reaction to generate cytotoxic hydroxyl radicals in tumor region has been widely investigated. Recently, the dendrimers featured with abundant surface functional groups and excellent biocompatibility are regarded as promising carriers of metal elements for tumor delivery. Much effort has been devoted to design dendrimer‐based nanodrugs for CDT and CDT‐involved synergistic therapy of tumors. Herein, the recent advances in the construction of dendrimer‐based nanodrugs (in most cases, poly(amidoamine) dendrimers) for CDT, CDT/chemotherapy, CDT/phototherapy, CDT/gene therapy, or CDT‐involved multimodal therapy are reviewed. Furthermore, the future perspectives with regard to the development of dendrimer‐based nanodrugs for CDT‐involved tumor treatment are also briefly discussed.

2D materials exhibit a variety of characteristics that make them appealing platforms for cancer treatment such as high drug loading capacity and photothermal and photodynamic properties. A key advantage of 2D material platforms for oncological applications is the ability to harness multiple modalities including drug delivery, photothermal therapy, photodynamic therapy, chemodynamic therapy, gene delivery, and immunotherapy approaches for improved efficacy. In this review, a comparison of the unique properties of different classes of 2D materials that enable their usage as platforms for multimodal therapy is provided. Further, the benefits and drawbacks of different platforms are also highlighted. Finally, current challenges and emerging opportunities for future development of 2D materials to further enable combination therapy and translation from the bench to clinical oncology applications are discussed.

Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu 2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half-life of ES by membrane-coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non-specific ES release. After internalization, ECNM dissociates via the glutathione-responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Tumor therapy has advanced significantly in recent years, but tumor cells can still evade and survive the treatment through various mechanisms. Notably, tumor cells use autophagy to sustain viability by removing impaired mitochondria and clearing excess reactive oxygen species (ROS). In this study, the aim is to amplify intracellular oxidative stress by inhibiting mitochondrial autophagic flux. Multisynergistic environmental-response nanoparticles (ERNs) are engineered by integrating gold nanoparticles and copper peroxide with borosilicate bioactive glass. The controlled release of copper and inhibition of autophagy flux triggered an overabundance and accumulation of oxidative stress within the tumor cells. This stress triggered immunogenic tumor cell death, believed to initiate a systemic immune response. The tumor microenvironment (TME) transitioned back to a normal physiological state as tumor cells are ablated. ERNs responded to the microenvironment changes by depositing hydroxyapatite on the surface and spontaneously enhancing bone regeneration. This innovative formulation facilitates the functional transition of ERNs from "anti-tumor therapy" to "biomineralization" that kills cancers and induces new bone formation. Overall, it is shown that the ERNs effectively eradicate cancers by utilizing chemodynamic therapy, starvation therapy, and immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) has become an emerging cancer treatment strategy with advantages of tumor-specificity, high selectivity, and low systemic toxicity. However, it usually suffers from low therapeutic efficacy. This is caused by low hydroxyl radical (·OH) yield arising because of the relatively high pH, overexpressed glutathione, and low H 2 O 2 concentration in the tumor microenvironment (TME). Herein, a probiotic metabolism-initiated pH reduction and H 2 O 2 supply-enhanced CDT strategy is reported to eradicate tumors by generating ·OH, in which Lactobacillus acidophilus is coupled with CoFeCe-layered double hydroxide nanosheets loaded with CaO 2 nanoparticles (NPs) as a chemodynamic platform for high-efficiency CDT (CaO 2 /LDH@L. acidophilus). Owing to the hypoxia tropism of L. acidophilus, CaO 2 /LDH@L. acidophilus exhibits increased accumulation at tumor sites compared with the CaO 2 /LDH. The CaO 2 NPs loaded on CoFeCe-LDH nanosheets are decomposed into H 2 O 2 in the TME. L. acidophilus metabolite-induced pH reduction (<5.5) and CaO 2 -mediated in situ H 2 O 2 generation synergistically boost ·OH generation activity of the CoFeCe-LDH nanosheets, effectively damaging cancer cells and ablating tumors with a tumor inhibition rate of 96.4%, 2.32-fold higher than that of CaO 2 /LDH. This work demonstrates that probiotics can function as a tumor-targeting platform to remodel the TME and amplify ROS generation for highly efficient and precise CDT., (© 2024 Wiley‐VCH GmbH.)

Bacterial infection of wound surfaces has posed a significant threat to human health and represents a formidable challenge in the clinical treatment. In this study, a novel antimicrobial hydrogel utilizing POM is synthesized as the primary component, with gelatin and sodium alginate as the structural framework. The resultant hydrogel demonstrates exceptional mechanical properties and viscoelasticity attributed to the hydrogen-bonded cross-linking between POM and gelatin, as well as the ionic cross-linking between sodium alginate and Ca 2+ . In addition, the integration of CuS nanoparticles conferred photothermal properties to the hydrogel system. To address the concerns regarding the potential thermal damage to the surrounding normal cells, this study employs a LT-PTT combined with CDT approach to achieve the enhanced antimicrobial efficacy while minimizing the inadvertent harm to the healthy cells. The findings suggested that POM-based hydrogels, serving as an inorganic-organic hybrid material, will represent a promising antimicrobial solution and offer valuable insights for the development of the non-antibiotic materials., (© 2024 Wiley‐VCH GmbH.)

Boron neutron capture therapy (BNCT) stands out as a noninvasive potential modality for invasive malignant tumors, with boron drugs playing a crucial role in its efficacy. Nevertheless, the development of boron drugs with biodegradability, as well as high permeability and retention effects, continues to present significant challenges. Here, we fabricate a size-tunable boron nanoreactor (TBNR) via assembling boron nitride quantum dots (BNQDs) and Fe3+ for tumor BNCT and chemodynamic (CDT) synergistic treatment. The obtained TBNR with an appropriate size exhibits superior tumor accumulation and retention. Upon stimulation by the tumor microenvironment (TME), the contained Fe3+ undergo redox reactions with glutathione (GSH) to produce Fe2+ Fenton reagents, which in turn activate CDT function and simultaneously induce TBNR depolymerization. Subsequently, the released ultrasmall BNQDs exhibit intra-deep penetration characteristic and are fully enriched at the tumor site. The in vivo experiments reveal that TBNR possesses excellent biocompatibility and superior synergistic anti-tumor ability post neutron irradiation, resulting in significant shrinkage of subcutaneous 4T1 tumors. Moreover, the TBNR-mediated BNCT has triggered an obvious immune response, which contributes to the long-term suppression of tumors after neutron irradiation. To conclude, this study provides a new approach for constructing more efficient versatile nanocarriers for BNCT-induced combination cancer therapies., (© 2024 Wiley‐VCH GmbH.)

Combining chemo/photodynamic therapy (CDT/PDT) to generate highly harmful reactive oxygen species and cause mitochondria dysfunction is considered a potential strategy to improve the efficiency of anticancer treatment. However, within tumor, the relatively deficient concentration of H 2 O 2 , hypoxic microenvironment, and overexpressed reduced glutathione (GSH) seriously suppress the efficacy of dynamic therapy. Herein, a multi-functional cascade nanoreactor, bovine serum albumin modified ZnO 2 @CeO 2 -ICG, is reported for remodeling tumor microenvironment (TME) to boost dynamic therapy and realize mitochondria dysfunction via reactive oxygen species (ROS) storm/Zn 2+ ions overload. Within TME, ZnO 2 decomposed into exogenous H 2 O 2 and Zn 2+ ion. The dual enzyme-like CeO 2 catalyzes the increased H 2 O 2 into ·OH and oxygen molecules respectively, and then the oxygen molecules are translated into 1 O 2 by indocyanine green (ICG) under 808 nm light irradiation to boost PDT. The effective consumption of GSH through the reduction of Ce(IV) ions not only regenerates Ce(III) ions to enhance the efficiency of CDT but also efficaciously alleviates the elimination of ROS generated by dynamic therapy to further improve dynamic therapeutic efficiency. So the improved ROS level under remodeling TME and Zn 2+ ions acutely lead to mitochondria dysfunction to boost the efficiency of antitumor treatment. Thus, developing functional nanoreactors that enable remodeling TME provides a potential strategy to enhance the efficiency of dynamic therapy., (© 2024 Wiley‐VCH GmbH.)

The development of theragnostic nanosystems integrating FRET (fluorescence resonance energy transfer) imaging and chemodynamic therapy (CDT) for accurate diagnosis and effective treatment of lung tumors is still a big challenge. Herein, a peptide-assembled 3D DNAzyme motor nanodevice is engineered for a self-powered FRET amplifier profiling human neutrophil elastase (HNE) and self-supplied H 2 O 2 enhancing CDT. The nanodevice is prepared by depositing AuNPs on ZIF-8, in which ZIF-8 co-loaded the lysosomal targeting peptide-modified copper peroxides (PCPs) and hairpins (H1, H2, and H3), AuNPs are co-labeled by DNAzyme-peptide (DP) conjugate and H3. In the tumor micro-environment, HNE driven 3D DNAzyme walker followed by an exponential amplification constructed by a synergistic cross-activation between hybridization chain reaction and DNAzyme, generating a self-powered FRET amplifier. The FRET amplifier specifically measures HNE with a sensitivity of 0.026 pM, and successfully images exogenous HNE in living cells and monitors HNE in mouse models. Moreover, the PCPs can target lysosomes, reducing lysosome escape. The self-supplying H 2 O 2 undertaken by PCPs improves the Cu (II)-catalyzed Fenton-like reaction, effectively causing cell apoptosis to inhibit tumor growth. Significantly, the nanodevice successfully screens inhibitors and discriminates the HNE level in normal and lung cancer tissues, suggesting that the nanodevice provides an effective tool for the diagnosis and treatment of lung tumors., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Herein, a ccRCC targeting nanodrug is designed to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd 2 O 3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx can be effectively internalized by Renca cells, open the "gate", and then release LOx and copper (Cu) ions. LOx can catalyze excessive lactate in Renca cells into H 2 O 2 , following that the produced H 2 O 2 is further converted by Cu ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive Cu ions effectively trigger tumor cuproptosis. These synergistic effects induce the release of damage associated molecular patterns (DAMPs) and activate immunogenic cell death (ICD), leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulates the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improves T 1 -weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrates that the mCGYL-LOx has great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is emerged as a novel and promising tumor therapy by using the powerful reactive oxygen species (ROS) to kill cancer cells. However, the current CDT is remarkably inhibited due to insufficient H 2 O 2 supply and over-expression of glutathione (GSH) in the tumor microenvironment (TME). Herein, a biodegradable self-supplying H 2 O 2 nano-enzyme of CuO 2 @CaP with a GSH-consumption effect is designed for cascade enhanced CDT to overcome the problem of H 2 O 2 deficiency and GSH overexpression. In this design, CuO 2 @CaP is gradually degraded to Ca 2+ , Cu 2+ , and H 2 O 2 in acidic TME, resulting in synergistically enhanced CDT owing to the efficient self-supplied H 2 O 2 and GSH-depletion and Ca 2+ overload therapy. Interestingly, the faster degradation of CuO 2 @CaP and promoted production rate of •OH are further achieved after triggering with ultrasound (US). And, the US-enhanced CDT and Ca 2+ overload synergistic antitumor therapy is successfully achieved in vivo. These findings provide a promising strategy for designing biodegradable nano-enzymes with self-supplying H 2 O 2 and GSH consumption for US-mediated CDT., (© 2024 Wiley‐VCH GmbH.)

Polymicrobial wound infection represents a significant contributor to infectious disease-related morbidity and mortality globally. Traditionally, the management of such infection relies heavily on high doses of antibiotics, often resulting in systemic side effects and exacerbating antibiotic resistance. Consequently, there is an urgent need to develop a safe and effective platform for antibiotic-free treatment of polymicrobial wound infections. In this study, a near-infrared (NIR) light-actuated nanofibrous membrane incorporating botanicals and nanozymes is presented for antibiotic-free triple-synergistic therapy against polymicrobial wound infections. The membrane integrates berberine hydrochloride (BBH)-loaded hollow zinc-doped carbon nanocubes into polyvinyl alcohol (PVA) nanofibrous membranes. Upon low-intensity 808 nm NIR laser irradiation (0.3 W cm -2 ), the membrane achieved a controlled release of BBH and enhanced peroxidase-like (POD-like) enzyme activity. This NIR light-actuated botanical/photothermal therapy (PTT)/chemodynamic therapy (CDT) system demonstrated high efficacy in eradicating methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa both in vitro and in vivo. Furthermore, it mitigated inflammation and promoted wound healing in polymicrobial infection wounds, highlighting its potential as a promising alternative to antibiotic-based therapies., (© 2024 Wiley‐VCH GmbH.)

As an intracellular protective mechanism, autophagy has the potential to significantly impair the therapeutic effects of photothermal therapy (PTT) and chemodynamic therapy (CDT), which helps cancer cells survive under harsh conditions, such as high temperature and reactive oxygen species (ROS). In this study, an autophagy blockage enhanced PTT and CDT synergistic therapy nanoplatform is constructed by loading hydroxychloroquine (HCQ) with autophagy inhibitory effect into hollow copper sulfide (HCuS). Specifically, HCuS produces toxic ROS through Fenton-like reaction in the tumor microenvironment (TME). At the same time, PTT-mediated temperature elevation of the tumor region accelerates the Fenton-like reaction and ROS production, enhancing the therapeutic effect of CDT. Furthermore, the internal autophagy inhibitor HCQ significantly blocks the fusion of autophagosomes and lysosomes by deacidifying lysosomes, cutting off the self-protection mechanism of cancer cells, and amplifying the combined treatment of PTT and CDT. Both in vitro and in vivo results demonstrate that the combination of photothermal-enhanced chemodynamic therapy with inhibition of autophagy provides new insights into designing multifunctional therapeutic nanoagents., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is an emerging therapeutic paradigm for cancer treatment that utilizes reactive oxygen species (ROS) to induce apoptosis of cancer cells but few biomaterials have been developed to differentiate the cancer cells and normal cells to achieve precise and targeted CDT. Herein, a simple cascade enzyme system is developed, termed hemin-micelles-GOx, based on hemin and glucose oxidase (GOx)-encapsulated Pluronic F127 (F127) micelles with pH-sensitive enzymatic activities. Histidine-tagged GOx can be easily chelated to hemin-F127 micelles via the coordination of histidine and ferrous ions in the center of hemin by simple admixture in an aqueous solution. In tumor microenvironment (TME), hemin-micelles-GOx exhibits enhanced peroxidase (POD)-like activities to generate toxic hydroxyl radicals due to the acidic condition, whereas in normal cells the catalase (CAT)-like, but not POD-like activity is amplified, resulting in the elimination of hydrogen peroxide to generate oxygen. In a murine melanoma model, hemin-micelles-GOx significantly suppresses tumor growth, demonstrating its great potential as a pH-mediated enzymatic switch for tumor management by CDT., (© 2024 Wiley‐VCH GmbH.)

Despite advancements in breast cancer treatment, bone metastases remain a significant concern for advanced breast cancer patients. Current theranostics strategies face challenges in integrating tumor theranostics and bone formation. Herein, this work develops an activatable targeted nanomedicine AuMnCO@BSA-N 3 (AMCBN) to enable a novel collaborative integration of second near-infrared (NIR-II) fluorescence imaging guided precise theranostics for breast cancer bone metastases and osteogenic microenvironment remolding. This strategy employs a chemical coordination between noble metal complex and metal carbonyl (MnCO), with surface modification of azide groups to enhance tumor affinity through passive and active targeting. The initiated respondent behavior of AMCBN by tumor microenvironment accelerate the degradation of coordinated MnCO, resulting in a rapid release of multifunctional agents for efficient chemodynamic therapy (CDT)/gas synergistic therapy. Meanwhile, the exceptional bone-binding properties enable the efficient and controlled release of Mn 2+ ions and carbon monoxide (CO) in the bone microenvironment, thereby facilitating the expression of osteogenesis-related proteins and establishing a novel synchronous theranostics process for tumor-bone repair., (© 2024 Wiley‐VCH GmbH.)

Persistent luminescence nanoparticles (PLNPs) can achieve autofluorescence-free afterglow imaging, while near-infrared (NIR) emission realizes deep tissue imaging. Nanozymes integrate the merits of nanomaterials and enzyme-mimicking activities with simple preparation. Here PLNPs are prepared of Zn 1.2 Ga 1.6 Ge 0.2 O 4 :Cr 0.0075 with NIR emission at 700 nm. The PLNPs are then incubated with IrCl 3 solution, and the nanoparticles are collected and annealed at 750 °C to obtain iridium@PLNPs. Iridium is observed on the PLNPs at the atomic level as a single-atom nanozyme with peroxidase-like catalytic activity, photothermal conversion, and computed tomography (CT) contrast capability. After coating with exosome membrane (EM), the Ir@PLNPs@EM composite exhibits long-lasting NIR luminescence, peroxidase-like catalytic activity, photothermal conversion, and CT contrast capability, with the targeting capability and biocompatibility from EM. Thus, NIR afterglow/photothermal/CT trimodal imaging-guided photothermal-chemodynamic combination therapy is realized as validated with the in vitro and in vivo inhibition of tumor growth, while toxicity and side effects are avoided as drug-free treatment. This work offers a promising avenue for advanced single-atom nanozyme@PLNPs to promote the development of nanozymes and PLNPs for clinical applications., (© 2024 Wiley‐VCH GmbH.)

We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)-to-Fe(II) photoreduction in Fe(III) metal-organic frameworks (MOFs) brings about the release of free Fe 2+ /Fe 3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre-passivated by SP. The release of free Fe 3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx-mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe 2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H 2 O 2 ), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (⋅OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor-bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects., (© 2024 Wiley-VCH GmbH.)

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen ( 1 O 2 ) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H 2 O 2 ), the therapeutic effect of which is highly dependent on the concentration of H 2 O 2 . Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1 O 2 and ⋅OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT., (© 2024 Wiley-VCH GmbH.)

Nanozymes have obvious advantages in improving the efficiency of cancer treatment. However, due to the lack of tissue specificity, low catalytic efficiency, and so on, their clinical applications are limited. Herein, the nanoplatform CeO 2 @ICG@GOx@HA (CIGH) with self-accelerated cascade reactions is constructed. The as-prepared nanozyme shows the superior oxidase (OXD)-like, superoxide dismutase (SOD)-like, catalase (CAT)-like and peroxidase (POD)-like activities. At the same time, under 808 nm near-infrared (NIR) irradiation, the photodynamic and photothermal capabilities are also significantly enhanced due to the presence of indocyanine green (ICG). We demonstrate that the nanozyme CIGH can efficiently accumulate in the tumor and exhibit amplified cascade antitumor effects with negligible systemic toxicity through the combination of photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT) and starvation therapy. The nanozyme prepared in this study provides a promising candidate for catalytic nanomedicines for efficient tumor therapy., (© 2024 Wiley-VCH GmbH.)

The immunosuppressive tumor microenvironment (TME) reduces the chimeric antigen receptor (CAR) T-cell therapy against solid tumors. Here, a CAR T cell membrane-camouflaged nanocatalyst (ACSP@TCM) is prepared to augment CAR T cell therapy efficacy against solid tumors. ACSP@TCM is prepared by encapsulating core/shell Au/Cu 2- x Se and 3-bromopyruvate with a CAR T cell membrane. It is demonstrated that the CAR T cell membrane camouflaging has much better-targeting effect than the homologous tumors cell membrane camouflaging. ACSP@TCM has an appealing synergistic chemodynamic/photothermal therapy (CDT/PTT) effect that can induce the immunogenic cell death (ICD) of NALM 6 cells. Moreover, 3-bromopyruvate can inhibit the efflux of lactic acid by inhibiting the glycolysis process, regulating the acidity of TME, and providing a more favorable environment for the survival of CAR T cells. In addition, the photoacoustic (PA) imaging and computed tomography (CT) imaging performance can guide the ACSP@TCM-mediated tumor therapy. The results demonstrated that the ACSP@TCM significantly enhanced the CAR T cell therapy efficacy against NALM 6 solid tumor mass, and completely eliminated tumors. This work provides an effective tumor strategy for CAR T cell therapy in solid tumors., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is a novel tumor treatment method by using hydroxyl radicals ( • OH) to kill cancer cells. However, its therapeutic effects are strictly confined by the short lifespan of • OH and reduced • OH generation speed. Herein, an effective CDT is achieved by both improving • OH lifetime and long-lasting generating • OH through intraparticle electron transfer within heterogeneous nanoparticles (NPs). These heterogeneous NPs are composed of evenly distributed Cu and Fe 3 O 4 (CFO NPs) with large interaction interfaces, and electrons tend to transfer from Cu to Fe 3 O 4 for the appearance of ≡Cu 2+ and increase in ≡Fe 2+ . The generated ≡Cu 2+ can interact with GSH, which prolongs the lifespan of • OH, produces ≡Cu + for higher speed • OH generation with H 2 O 2 , and induces cell ferroptosis for tumor therapy. The improved ≡Fe 2+ can also improve the • OH release under H 2 O 2 until Cu is depleted. As a result, a sustainable • OH generation is achieved to promote cell apoptosis for effective tumor therapy. Since H 2 O 2 and GSH are only overexpressed at tumor, and CFO NPs can degrade in the tumor microenvironment, these NPs are with high biosafety and can be metabolized by urine. This work provides a novel biomaterial for effective cancer CDT through intraparticle electron transfer., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Compromises between enhanced on-targeting reactivity and precise real-time monitoring in the tumor microenvironment (TME) are the main roadblocks for catalytic cancer therapy. The hallmark of a high level of hydrogen peroxide (H 2 O 2 ) and acidic extracellular environment of the hypoxia solid tumor can underpin therapeutic and tracking performance. Herein, this work provides an activatable wintersweet-like nanohybrid consisting of titanium (Ti) doped cerium vanadate nanorods with the modification of polypyrrole (PPy) nanoparticles (CeVO 4 -Ti@PPy) for combinatorial therapies of breast carcinoma. The Ti dopants in the size-controllable CeVO 4 nanorods lower the energy barrier (0.5 eV) of the rate-determining steps and elaborate peroxidase-like (POD-like) activities to improve the generation of toxic hydroxyl radical (·OH) according to the density functional theory (DFT) calculation. The multiple enzyme-like activities, including the intrinsic glutathione peroxidase (GPx) and catalase (CAT), achieve a record-high therapeutic efficiency. Coupling this oxidative stress with the photothermal effects of PPy enables enhanced catalytic tumor necrosis. The exterior PPy heterogeneous structure can be further doped with protons in the local acidic environment to intensify photoacoustic signals, allowing the non-invasive accurate tracking of tumors. The theranostic performance displayed negligible attenuated signals in near-infrared (NIR) windows. This organic-inorganic nanohybrid with a heterogeneous structure provides the potential to improve the overall outcomes of catalytic therapy., (© 2024 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment., (© 2024 Wiley‐VCH GmbH.)

Catalytic nanoparticles (CNPs) as heterogeneous catalyst reveals superior activity due to their physio-chemical features, such as high surface-to-volume ratio and unique optical, electric, and magnetic properties. The CNPs, based on their physio-chemical nature, can either increase the reactive oxygen species (ROS) level for tumor and antibacterial therapy or eliminate the ROS for cytoprotection, anti-inflammation, and anti-aging. In addition, the catalytic activity of nanozymes can specifically trigger a specific reaction accompanied by the optical feature change, presenting the feasibility of biosensor and bioimaging applications. Undoubtedly, CNPs play a pivotal role in pushing the evolution of technologies in medical and clinical fields, and advanced strategies and nanomaterials rely on the input of chemical experts to develop. Herein, a systematic and comprehensive review of the challenges and recent development of CNPs for biomedical applications is presented from the viewpoint of advanced nanomaterial with unique catalytic activity and additional functions. Furthermore, the biosafety issue of applying biodegradable and non-biodegradable nanozymes and future perspectives are critically discussed to guide a promising direction in developing span-new nanozymes and more intelligent strategies for overcoming the current clinical limitations., (© 2024 Wiley‐VCH GmbH.)

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe 2 O 4 @TiO 2 @CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe 2 O 4 @TiO 2 could produce 1 O 2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H 2 O 2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy., (© 2024 Wiley‐VCH GmbH.)

Ferroptosis is an iron-dependent and lipid peroxides (LPO)-overloaded programmed damage cell death, induced by glutathione (GSH) depletion and glutathione peroxide 4 (GPX4) inactivation. However, the inadequacy of endogenous iron and reactive oxygen species (ROS) restricts the efficacy of ferroptosis. To overcome this obstacle, a near-infrared photo-responsive FeP@PEG NPs is fabricated. Exogenous iron pool can enhance the effect of ferroptosis via the depletion of GSH and further regulate GPX4 inactivation. Generation of ·OH derived from the Fenton reaction is proved by increased accumulation of lipid peroxides. The heat generated by photothermal therapy and ROS generated by photodynamic therapy can enhance cell apoptosis under near-infrared (NIR-808 nm) irradiation, as evidenced by mitochondrial dysfunction and further accumulation of lipid peroxide content. FeP@PEG NPs can significantly inhibit the growth of several types of cancer cells in vitro and in vivo, which is validated by theoretical and experimental results. Meanwhile, FeP@PEG NPs show excellent T2-weighted magnetic resonance imaging (MRI) property. In summary, the FeP-based nanotheranostic platform for enhanced phototherapy/ferroptosis/chemodynamic therapy provides a reliable opportunity for clinical cancer theranostics., (© 2024 Wiley‐VCH GmbH.)

Cancer is indisputably one of the major threats to mankind, and hence the design of new approaches for the improvement of existing therapeutic strategies is always wanted. Herein, the design of a tumor microenvironment-responsive, DNA-based chemodynamic therapy (CDT) nanoagent with dual Fenton reaction centers for targeted cancer therapy is reported. Self-assembly of DNA amphiphile containing copper complex as the hydrophobic Fenton reaction center results in the formation of CDT-active DNAsome with Cu 2+ -based Fenton catalytic site as the hydrophobic core and hydrophilic ssDNA protrude on the surface. DNA-based surface addressability of the DNAsome is then used for the integration of second Fenton reaction center, which is a peroxidase-mimicking DNAzyme noncovalently loaded with Hemin and Doxorubicin, via DNA hybridization to give a CDT agent having dual Fenton reaction centers. Targeted internalization of the CDT nanoagent and selective generation of • OH inside HeLa cell are also shown. Excellent therapeutic efficiency is observed for the CDT nanoagent both in vitro and in vivo, and the enhanced efficacy is attributed to the combined and synergetic action of CDT and chemotherapy., (© 2024 Wiley‐VCH GmbH.)

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment., (© 2024 Wiley‐VCH GmbH.)

Chirality is a prevalent characteristic in nature, where biological systems exhibit a significant preference for specific enantiomers of biomolecules. However, there is a limited exploration into utilizing nanomaterials' chirality to modulate their interactions with intracellular substances. In this study, self-assembled copper-cysteine chiral nanoparticles and explore the influence of their charity on cancer chemodynamic therapy (CDT) are fabricated. Experimental and molecular dynamics (MD) simulation results demonstrate that the copper-l-cysteine chiral nanoparticles (Cu-l-Cys NPs) exhibit a stronger affinity toward l-glutathione (l-GSH) that is overproduced in cancer cells, compared to the copper-d-cysteine enantiomer (Cu-d-Cys NPs). The interaction between Cu-l-Cys NPs and l-GSH triggers a redox reaction that depletes l-GSH and converts Cu 2+ into Cu + . Subsequently, Cu + catalyzes a Fenton-like reaction, decomposing H 2 O 2 into highly cytotoxic hydroxyl radicals (•OH) for cancer CDT. In vivo, results confirm that Cu-l-Cys NPs with good biocompatibility elicit a pronounced cancer cell death and effectively inhibit tumor growth. This work proposes a new perspective on chirality-enhanced cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Pyroptosis, a new mode of regulatory cell death, holds a promising prospect in tumor therapy. The occurrence of pyroptosis can trigger the release of damage-associated molecular patterns (DAMPs) and activate the antitumor immune response. Moreover, enhancing intracellular reactive oxygen species (ROS) generation can effectively induce pyroptosis. Herein, an integrated nanoplatform (hCZAG) based on zeolitic imidazolate framework-8 (ZIF-8) with Cu 2+ and Zn 2+ as active nodes and glucose oxidase (GOx) loading is constructed to evoke pyroptosis. GOx can effectively elevate intracellular hydrogen peroxide (H 2 O 2 ) levels to regulate the unfavorable tumor microenvironment (TME). Cu 2+ can be reduced to Cu + by endogenous overexpressed GSH and both Cu 2+ and Cu + can exert Fenton-like activity to promote ROS generation and amplify oxidative stress. In addition, the accumulation of Cu 2+ leads to the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), thus resulting in cuproptosis. Notably, the outburst of ROS induced by hCZAG activates Caspase-1 proteins, leads to the cleavage of gasdermin D (GSDMD), and induces pyroptosis. Pyroptosis further elicits an adaptive immune response, leading to immunogenic cell death (ICD). This study provides effective strategies for triggering pyroptosis-mediated immunotherapy and achieving improved therapeutic effects., (© 2024 Wiley‐VCH GmbH.)

Abstract An ultrasmall chemodynamic therapeutic (CDT) agent with favorable specificity to tumor microenvironment, i.e., high level of glutathione (GSH) and hydrogen peroxide (H2O2), is reported. The coordination polymer nanodot between divalent copper (Cu2+) and gallic acid (GA) is shortly named as Cu–GA. The ultrasmall size of Cu–GA (2.16 ± 0.3 nm) results in a large specific surface area, which is beneficial for improving its catalytic performance. After endocytosis into tumor cell interior, Cu–GA promotes GSH‐activated and H2O2‐reinforced CDT in situ, wherein divalent Cu(II) is reduced to monovalent Cu(I) by GSH and induced GSH depletion. Subsequently, the generated Cu(I) catalyzes local H2O2 to generate toxic hydroxyl radical (•OH) via Fenton‐like reaction, and •OH leads to tumor cell apoptosis. The higher levels of GSH and H2O2 in the tumor cell interior significantly improve the efficiency of CDT, and meanwhile protect the normal cells. In addition, the ultrasmall size of Cu–GA facilitates its fast clearance and eliminates long‐term body retention, with minimized systemic toxicity during the treatment in vivo. Therefore, as a novel copper‐based nanoformulation specifically responsive to the tumor microenvironment, Cu–GA provides promising potentials in CDT.

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are promising tumor treatments mediated by reactive oxygen species (ROS), which have the advantages of being minimally invasive. However, the hypoxia of tumor microenvironment and poor target ability often reduce the therapeutic effect. Here we propose a tumor targeted nanoplatform PCN-224@Co 3 O 4 -HA for enhanced PDT and synergistic CDT, constructed by hyaluronate-modified Co 3 O 4 nanoparticles decorated metal-organic framework PCN-224. Co 3 O 4 can catalyze the decomposition of highly expressed H 2 O 2 in tumor cells to produce oxygen and alleviate the problem of hypoxia. It can also produce hydroxyl radicals according to the Fenton-like reaction for chemical dynamic therapy, significantly improving the therapeutic effect. The cell survival experiment showed that after in vitro treatment, 4T1 and MCF-7 cancer cells died in a large area under the anaerobic state, while the survival ability of normal cell L02 was nearly unchanged. This result effectively indicated that PCN-224@Co 3 O 4 -HA could effectively relieve tumor hypoxia and improve the effect of PDT and synergistic CDT. Cell uptake experiments showed that PCN-224@Co 3 O 4 -HA had good targeting properties and could effectively aggregate in tumor cells. In vivo experiments on mice, PCN-224@Co 3 O 4 -HA presented reliable biosafety performance, and can cooperate with PDT and CDT therapy to prevent the growth of tumor., (© 2024 Wiley-VCH GmbH.)

Customizable and number-tunable enzyme delivery nanocarriers will be useful in tumor therapy. Herein, a phage vehicle, T4-Lox-DNA-Fe (TLDF), which adeptly modulates enzyme numbers using phage display technology to remodel the tumor microenvironment (TME) is presented. Regarding the demand for lactic acid in tumors, each phage is engineered to display 720 lactate oxidase (Lox), contributing to the depletion of lactic acid to restructure the tumor's energy metabolism. The phage vehicle incorporated dextran iron (Fe) with Fenton reaction capabilities. H 2 O 2 is generated through the Lox catalytic reaction, amplifying the H 2 O 2 supply for dextran iron-based chemodynamic therapy (CDT). Drawing inspiration from the erythropoietin (EPO) biosynthetic process, an EPO enhancer is constructed to impart the EPO-Keap1 plasmid (DNA) with tumor hypoxia-activated functionality, disrupting the redox homeostasis of the TME. Lox consumes local oxygen, and positive feedback between the Lox and the plasmid promotes the expression of kelch ECH Associated Protein 1 (Keap1). Consequently, the downregulation of the antioxidant transcription factor Nrf2, in synergy with CDT, amplifies the oxidative killing effect, leading to tumor suppression of up to 78%. This study seamlessly integrates adaptable T4 phage vehicles with bio-intelligent plasmids, presenting a promising approach for tumor therapy., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Interfering with intratumoral metabolic processes is proven to effectively sensitize different antitumor treatments. Here, a tumor-targeting catalytic nanoplatform (CQ@MIL-GOX@PB) loading with autophagy inhibitor (chloroquine, CQ) and glucose oxidase (GOX) is fabricated to interfere with the metabolisms of tumor cells and tumor-associated macrophages (TAMs), then realizing effective antitumor chemodynamic therapy (CDT). Once accumulating in the tumor site with the navigation of external biotin, CQ@MIL-GOX@PB will release Fe ions and CQ in the acid lysosomes of tumor cells, the latter can sensitize Fe ions-involved antitumor CDT by blocking the autophagy-dependent cell repair. Meanwhile, the GOX component will consume glucose, which not only generates many H 2 O 2 for CDT but also once again decelerates the tumor repair process by reducing energy metabolism. What is more, the release of CQ can also drive the NO anabolism of TAMs to further sensitize CDT. This strategy of multiple metabolic regulations is evidenced to significantly improve the antitumor effect of traditional CDT nanoagents and might provide a new sight to overcome the bottlenecks of different antitumor treatments., (© 2024 Wiley‐VCH GmbH.)

Given the challenge of multidrug resistance in antibiotics, non-antibiotic-dependent antibacterial strategies show promise for anti-infective therapy. V 2 C MXene-based nanomaterials have demonstrated strong biocompatibility and photothermal conversion efficiency (PCE) for photothermal therapy (PTT). However, the limitation of V 2 C MXene's laser irradiation to the near-infrared region I (NIR-I) restricts tissue penetration, making it difficult to achieve complete bacterial eradication with single-effect therapeutic strategies. To address this, Pt nanoparticles (Pt NPs) are attached to V 2 C, forming artificial nanoplatforms (Pt@V 2 C). Pt@V 2 C exhibits enhanced PCE (59.6%) and a longer irradiation laser (NIR-II) due to the surface plasmon resonance effect of Pt NPs and V 2 C. Notably, Pt@V 2 C displays dual enzyme-like activity with chemodynamic therapy (CDT) and NIR-II enhanced dual enzyme-like activity. The biocatalytic mechanism of Pt@V 2 C is elucidated using density functional theory. In an in vivo animal model, Pt@V 2 C effectively eliminates methicillin-resistant Staphylococcus aureus from deep-seated tissues in subcutaneous abscesses and bacterial keratitis environments, accelerating abscess resolution and promoting wound and cornea healing through the synergistic effects of PTT/CDT. Transcriptomic analysis reveals that Pt@V 2 C targets inflammatory pathways, providing insight into its therapeutic mechanism. This study presents a promising therapeutic approach involving hyperthermia-amplified biocatalysis with Pt NPs and MXene nanocomposites., (© 2024 Wiley‐VCH GmbH.)

Metal-organic framework (MOF)-based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti-tumor therapy strategy by promoting the Fenton reaction by using core-shell zeolitic imidazolate framework-8 (ZIF-8)@Fe 3 O 4 as a therapeutic platform is proposed. Carboxymethyl cellulose (CMC) is used as a stabilizer of Fe 3 O 4 , which is then decorated on the surface of ZIF-8 via the electrostatic interaction and serves as an efficient Fenton reaction trigger. Meanwhile, the pH-responsive ZIF-8 scaffold acts as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX-ZIF-8@Fe 3 O 4 /CMC (DZFC) nanoparticles concomitantly accelerate DOX release and generate more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger glutathione peroxidase 4 (GPX4)-dependent ferroptosis via the activation of the c-Jun N-terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti-tumor efficacy. No marked toxic effects are detected during DZFC treatment in a tumor-bearing mouse model. This composite nanoparticle remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines., (© 2024 Wiley‐VCH GmbH.)

Bioenergetic therapy is emerging as a promising therapeutic approach. However, its therapeutic effectiveness is restricted by metabolic plasticity, as tumor cells switch metabolic phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) to compensate for energy. Herein, Metformin (MET) and BAY-876 (BAY) co-loaded CuFe 2 O 4 (CF) nanoplatform (CFMB) is developed to boost energy deprivation by synchronous interventions of glycolysis and OXPHOS for bioenergetic therapy synergetic with chemodynamic/photothermal therapy (CDT/PTT). The MET can simultaneously restrain glycolysis and OXPHOS by inhibiting hexokinase 2 (HK2) activity and damaging mitochondrial function to deprive energy, respectively. Besides, BAY blocks glucose uptake by inhibiting glucose transporter 1 (GLUT1) expression, further potentiating the glycolysis repression and thus achieving much more depletion of tumorigenic energy sources. Interestingly, the upregulated antioxidant glutathione (GSH) in cancer cells triggers CFMB degradation to release Cu + /Fe 2+ catalyzing tumor-overexpressed H 2 O 2 to hydroxyl radical (∙OH), both impairing OXPHOS and achieving GSH-depletion amplified CDT. Furthermore, upon near-infrared (NIR) light irradiation, CFMB has a photothermal conversion capacity to kill cancer cells for PTT and improve ∙OH production for enhanced CDT. In vivo experiments have manifested that CFMB remarkably suppressed tumor growth in mice without systemic toxicity. This study provides a new therapeutic modality paradigm to boost bioenergetic-related therapies., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Implant-associated osteomyelitis (IAOM) is characterized by bone infection and destruction; current therapy of antibiotic treatment and surgical debridement often results in drug resistance and bone defect. It is challenging to develop an antibiotic-free bactericidal and osteogenic-enhanced strategy for IAOM. Herein, an IAOM-tailored antibacterial and osteoinductive composite of copper (Cu)-strontium (Sr) peroxide nanoparticles (CSp NPs), encapsulated in polyethylene glycol diacrylate (PEGDA) (CSp@PEGDA), is designed. The dual functional CSp NPs display hydrogen peroxide (H 2 O 2 ) self-supplying and Fenton catalytic Cu 2+ ions' release, generating plenty of hydroxyl radical ( • OH) in a pH-responsive manner for bacterial killing, while the released Sr 2+ promotes the in vitro osteogenicity regarding cell proliferation, alkaline phosphatase activity, extracellular matrix calcification, and osteo-associated genes expression. The integration of Cu 2+ and Sr 2+ in CSp NPs together with the coated PEGDA hydrogel ensures the stable and sustainable ion release during short- and long-term periods. Benefitted from the injectablity and photo-crosslink ability, CSp@PEGDA is able to thoroughly fill the infectious site and gelate in situ for bacterial elimination and bone regeneration, which is verified through in vivo evaluation using a clinical-simulating IAOM mouse model. These favorable abilities of CSp@PEGDA precisely meet the multiple therapeutic needs and pave a promising way for implant-associated osteomyelitis treatment., (© 2024 Wiley‐VCH GmbH.)

Mild-heat photothermal antibacterial therapy avoids heat-induced damage to normal tissues but causes bacterial tolerance. The use of photothermal therapy in synergy with chemodynamic therapy is expected to address this issue. Herein, two pseudo-conjugated polymers P M123 with photothermal units and P Fc with ferrocene (Fc) units are designed to co-assemble with DSPE-mPEG 2000 into nanoparticle NP M123/Fc . NP M123/Fc under 1064 nm laser irradiation (NP M123/Fc +NIR-II) generates mild heat and additionally more toxic ∙OH from endogenous H 2 O 2 , displaying a strong synergistic photothermal and chemodynamic effect. NP M123/Fc +NIR-II gives >90% inhibition rates against MDR ESKAPE pathogens in vitro. Metabolomics analysis unveils that NP M123/Fc +NIR-II induces bacterial metabolic dysregulation including inhibited nucleic acid synthesis, disordered energy metabolism, enhanced oxidative stress, and elevated DNA damage. Further, NP M123/Fc +NIR-II possesses >90% bacteriostatic rates at infected wounds in mice, resulting in almost full recovery of infected wounds. Immunodetection and transcriptomics assays disclose that the therapeutic effect is mainly dependent on the inhibition of inflammatory reactions and the promotion of wound healing. What is more, thioketal bonds in NP M123/Fc are susceptible to ROS, making it degradable with highly favorable biosafety in vitro and in vivo. NP M123/Fc +NIR-II with a unique synergistic antibacterial strategy would be much less prone to select bacterial resistance and represent a promising antibiotics-alternative anti-infective measure., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The clinical application of oncology therapy is hampered by high glutathione concentrations, hypoxia, and inefficient activation of cell death mechanisms in cancer cells. In this study, Fe and Mo bimetallic sulfide nanomaterial (FeS 2 @MoS 2 ) based on metal-organic framework structure is rationally prepared with peroxidase (POD)-, catalase (CAT)-, superoxide dismutase (SOD)-like activities and glutathione depletion ability, which can confer versatility for treating tumors and mending wounds. In the lesion area, FeS 2 @MoS 2 with SOD-like activity can facilitate the transformation of superoxide anions (O 2 - ) to hydrogen peroxide (H 2 O 2 ), and then the resulting H 2 O 2 serves as a substrate for the Fenton reaction with FMS to produce highly toxic hydroxyl radicals (∙OH). Simultaneously, FeS 2 @MoS 2 has an ability to deplete glutathione (GSH) and catalyze the decomposition of nicotinamide adenine dinucleotide phosphate (NADPH) to curb the regeneration of GSH from the source. Thus it can realize effective tumor elimination through synergistic apoptosis-ferroptosis strategy. Based on the alteration of the H 2 O 2 system, free radical production, glutathione depletion and the alleviation of hypoxia in the tumor microenvironment, FeS 2 @MoS 2 NPS can not only significantly inhibit tumors in vivo and in vitro, but also inhibit multidrug-resistant bacteria and hasten wound healing. It may open the door to the development of cascade nanoplatforms for effective tumor treatment and overcoming wound infection., (© 2023 Wiley‐VCH GmbH.)

Specific activation of transient receptor potential vanilloid member 1 (TRPV1) channels provides a new avenue for cancer treatment by inducing excessive Ca 2+ influx. However, controllable manipulation of TRPV1 signaling for clinical application has remained elusive due to the challenge in finding a mild and effective method of exerting external stimulus without adverse side effects in living systems. Herein, a TRPV1-targeting near-infrared (NIR) triggered nitric oxide (NO)-releasing nanoplatform (HCuS@PDA-TRPV1/BNN6) based on polydopamine (PDA) coated hollow copper sulfide nanoparticles (HCuS NPs) is developed for specific cancer therapy. Upon NIR irradiation, the NO donor BNN6 encapsulated in NIR-responsive nanovehicles can locally generate NO to activate TRPV1 channels and induce Ca 2+ influx. This NIR controlled mode enables the nanoplatform to exert its therapeutic effects below the apoptotic threshold temperature (43°C), minimizing the photothermal damage to normal tissue. Integrating this special NO-mediated therapy with HCuS NPs mediated chemodynamic therapy, the designed nanoplatform exhibits a boosted anticancer activity with negligible systematic toxicity. Together, this study provides a promising strategy for site-specific cancer therapy by spatiotemporally controlled activation of surface ion channels, thus offering a solution to an unmet clinical need in cancer treatment., (© 2024 Wiley‐VCH GmbH.)

Nanotechnology profoundly affects the advancement of medicine. Limitations in diagnosing and treating cancer and chronic diseases promote the growth of nanomedicine. However, there are very few analytical and descriptive studies regarding the trajectory of nanomedicine, key research powers, present research landscape, focal investigative points, and future outlooks. Herein, articles and reviews published in the Science Citation Index Expanded of Web of Science Core Collection from first January 2000 to 18th July 2023 are analyzed. Herein, a bibliometric visualization of publication trends, countries/regions, institutions, journals, research categories, themes, references, and keywords is produced and elaborated. Nanomedicine-related academic output is increasing since the COVID-19 pandemic, solidifying the uneven global distribution of research performance. While China leads in terms of publication quantity and has numerous highly productive institutions, the USA has advantages in academic impact, commercialization, and industrial value. Nanomedicine integrates with other disciplines, establishing interdisciplinary platforms, in which drug delivery and nanoparticles remain focal points. Current research focuses on integrating nanomedicine and cell ferroptosis induction in cancer immunotherapy. The keyword "burst testing" identifies promising research directions, including immunogenic cell death, chemodynamic therapy, tumor microenvironment, immunotherapy, and extracellular vesicles. The prospects, major challenges, and barriers to addressing these directions are discussed., (© 2024 Wiley‐VCH GmbH.)

The combination of microwave ablation (MWA) and chemodynamic therapy (CDT) presents a promising strategy for complete eradication of residual tumor after MWA. However, it remains challenging and urgent to develop a facile, biocompatible, and imaging-guided platform for the achievement of this goal. Herein, a minimalist manganese hydrogel (ALG-Mn hydrogel) is proposed for synergistic MWA and CDT to completely eradicate tumor in vivo. The ALG-Mn hydrogel is prepared using a simple mixing method and exhibits excellent syringeability, remarkable microwave sensitivity, and potent Fenton-like activity. By assisting in MWA procedures, the ALG-Mn hydrogel enables both elimination of primary tumor mass through enhanced MWA efficacy and eradication of potential residual tumor tissues via robust CDT. This approach achieves complete tumor clearance without additional drug loading. Furthermore, the paramagnetic Mn 2+ component allows real-time dynamic visualization of the ALG-Mn hydrogel at the tumor site via magnetic resonance imaging. To the best of knowledge, the proposed ALG-Mn hydrogel represents the minimalist biocompatible platform for imaging-guided synergistic MWA and CDT toward achieving complete tumor clearance., (© 2024 Wiley‐VCH GmbH.)

Despite their unique characteristics, 2D MXenes with sole photothermal conversion ability are required to explore their superfluous abilities in biomedicine. The small-molecule-based chemotherapeutics suffer from various shortcomings of time-consuming and expensiveness concerning theoretical and performance (preclinical/clinical) checks. This study demonstrates the fabrication of Ti 3 C 2 MXene nanosheets (TC-MX NSs) and subsequent decoration with transition metal oxides, that is, copper oxide (Cu 2 O/MX, CO-MX NCs) as drugless nanoarchitectonics for synergistic photothermal (PTT)-chemodynamic therapeutic (CDT) efficacies. Initially, the monolayer/few-layered TC-MX NSs are prepared using the chemical etching-assisted ultrasonic exfoliation method and then deposited with Cu 2 O nanoconstructs using the in situ reduction method. Further, the photothermal ablation under near-infrared (NIR)-II laser irradiation shows PTT effects of CO-MX NCs. The deposited Cu 2 O on TC-MX NSs facilitates the release of copper (Cu + ) ions in the acidic microenvironment intracellularly for Fenton-like reaction-assisted CDT effects and enriched PTT effects synergistically. Mechanistically, these deadly free radicals intracellularly imbalance the glutathione (GSH) levels and result in mitochondrial dysfunction, inducing apoptosis of 4T1 cells. Finally, the in vivo investigations in BALB/c mice confirm the substantial ablation of breast carcinoma. Together, these findings demonstrate the potential synergistic PTT-CDT effects of the designed CO-MX NCs as drugless nanoarchitectonics against breast carcinoma., (© 2024 Wiley‐VCH GmbH.)

Copper-based nanozymes exhibit excellent antitumor activity but are easily inactivated due to the disturbance of proteins or other macromolecules with sulfhydryl. A tumor microenvironment-responsive CuMnO@Fe 3 O 4 (CMF) core-shell nanozyme for highly efficient tumor theranostics is developed. A platelet-derived growth factor receptor-β-recognizing cyclic peptide (PDGFB) target is conjugated to the surface of CMF to fabricate a tumor-specific nanozyme (PCMF). The core-shell nanostructure significantly avoids the oxidation and inactivation of copper-based nanozyme, promoting the antitumor activity of PCMF. The weak acid- and GSH-activated T 1 and T 2 relaxation rate of PCMF contributes to T 1 and T 2 dual contrast imaging at the tumor site. In addition, the PCMF disintegrates and produces some metal ions that possess Fenton catalytic activity (i.e., Cu + , Mn 2+ , and Fe 2+ ) under TME. This process significantly depletes GSH, accelerates Fenton and Fenton-like reactions, enhances cellular reactive oxygen species (ROS) levels, and induces cancer cell apoptosis and ferroptosis. PCMF also exhibits photothermal functions, so it can be used in combined photothermal therapy, ferroptosis therapy, and chemodynamic therapy, improving anticancer activity. This work provides insights into the design of an exquisite nanostructure for high-sensitive and tumor-specific theranostics., (© 2023 Wiley‐VCH GmbH.)

Chemodynamic therapy (CDT) is a particular oncological therapeutic strategy by generates the highly toxic hydroxyl radical (•OH) from the dismutation of endogenous hydrogen peroxide (H 2 O 2 ) via Fenton or Fenton-like reactions. However, single CDT therapies have been limited by unsatisfactory efficacy. Enhanced chemodynamic therapy (ECDT) triggered by near-infrared (NIR) is a novel therapeutic modality based on light energy to improve the efficiency of Fenton or Fenton-like reactions. However, the limited penetration and imaging capability of the visible (400-650 nm) and traditional NIR-I region (650-900 nm) light-amplified CDT restrict the prospects for its clinical application. Combined with the high penetration/high precision imaging characteristics of the second near-infrared (NIR-II,) nanoplatform, it is expected to kill deep tumors efficiently while imaging the treatment process in real-time, and more notably, the NIR-II region radiation with wavelengths above 1000 nm can minimize the irradiation damage to normal tissues. Such NIR-II ECDT nanoplatforms have greatly improved the effectiveness of CDT therapy and demonstrated extraordinary potential for clinical applications. Accordingly, various strategies have been explored in the past years to improve the efficiency of NIR-II Enhanced CDT. In this review, the mechanisms and strategies used to improve the performance of NIR-II-enhanced CDT are outlined., (© 2023 Wiley‐VCH GmbH.)

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO 2 ) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO 2 and Cu 2+ in the tumor microenvironment. The exposed CaO 2 further yields hydrogen peroxide (H 2 O 2 ) and Ca 2+ in a weakly acidic environment to strengthen the Cu 2+ -based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca 2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO 2 @DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O 2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues., (© 2023 Wiley‐VCH GmbH.)

Sonodynamic therapy (SDT) offers a remarkable non-invasive ultrasound (US) treatment by activating sonosensitizer and generating reactive oxygen species (ROS) to inhibit tumor growth. The development of multifunctional, biocompatible, and highly effective sonosensitizers remains a current priority for SDT. Herein, the first report that Mn(II) ions chelated Gd-TCPP (GMT) nanosheets (NSs) are synthesized via a simple reflux method and encapsulated with pluronic F-127 to form novel sonosensitizers (GMTF). The GMTF NSs produce a high yield of ROS under US irradiation due to the decreased highest occupied molecular orbital-lowest unoccupied molecular orbital gap energy (2.7-1.28 eV). Moreover, Mn(II) ions endow GMTF with a fascinating Fenton-like activity to produce hydroxyl radicals in support of chemodynamic therapy (CDT). It is also effectively used in magnetic resonance imaging (MRI) with high relaxation rate (r 1 : 4.401 mM -1  s -1 ) to track the accumulation of NSs in tumors. In vivo results indicate that the SDT and CDT in combination with programmed cell death protein 1 antibody (anti-PD-1) show effective metastasis prevention effects, and 70% of the mice in the GMTF + US + anti-PD-1 group survived for 60 days. In conclusion, this study develops a sonosensitizer with promising potential for utilizing both MRI-guided SDT and CDT strategies., (© 2023 Wiley‐VCH GmbH.)