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Reactive oxygen species (ROS) mediated cancer therapy has attracted tremendous interest. Nevertheless, the overexpression of intratumoral glutathione (GSH) reduced the oxidative stress and suppressed the efficiency of ROS-based dynamic anticancer treatment. Herein, a degradable nanocomposite, Fe-(SS)-MOF@BSO/Ce6@HA (FMBCH), was developed based on a hyaluronic acid-decorated metal–organic framework with encapsulated l-buthionine sulfoximine (BSO) and chlorin e6 (Ce6) for enhanced PDT and CDT. Once accumulated at the tumor region, the original GSH would be depleted via the redox reaction between GSH and S–S bonds and Fe3+ in FMBCH, leading to the decomposition of the nanoplatform and release of Fe2+, Ce6, and BSO. Fe2+ would catalyze endogenous H2O2 to lethal hydroxyl radicals (•OH), and Ce6 would convert oxygen to 1O2 under irradiation, inducing the death of cancer cells via the cooperation of CDT and PDT. Furthermore, BSO could suppress the GSH biosynthesis and downregulate glutathione peroxidase 4 (GPX4) expression, resulting in the excessive accumulation of lipid peroxidation (LPO). The in vitro and in vivo studies demonstrated that FMBCH could promote the therapeutic effect of CDT and PDT benefiting from its excellent multistage GSH depletion property. The engineered nanosystem provided a promising strategy for improving ROS-based antitumor efficiency via integrating the dual GSH elimination approach. [ABSTRACT FROM AUTHOR]

Versatile all-in-one nanoplatforms, which combine a variety of therapeutic and diagnostic capabilities, possess interesting physiochemical and biological characteristics, making them highly attractive in cancer-related biomedical applications. However, up to now, the precise design of nanocomposites with multiple functions has remained an ongoing challenge. Herein, this study constructed a tumor microenvironment (TME)-responsive nanocomposite therapeutic platform with a core–shell structure using bismuth (Bi) as the core and iron-porphyrin-containing covalent–organic polymers (COPs) as the shell. Under the irradiation of an 808 nm laser, Bi efficiently inhibits tumor cell growth through photothermal therapy (PTT), and porphyrin-based COPs can produce reactive oxygen species (ROS) by photodynamic therapy (PDT) under the irradiation of a 660 nm laser combined with chemodynamic therapy (CDT). Meanwhile, Bi as a green metal with good biocompatibility also has the potential for use in X-ray computed tomography (CT) imaging and near-infrared (NIR) thermal imaging. Therefore, this nanocomposite integrated multifunctional treatment pathways (PTT, PDT, and CDT) and multimodel (CT and NIR) imaging to cope with the complexity and diversity of tumor cells, effectively improving therapeutic efficacy and becoming a potential candidate for tumor diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In this study, a fascinating nanoplatform, possessing fluorescent imaging, hyperthermia-amplified reactive oxygen species (ROS) generation, and calcium-overloaded comediated multimodal therapeutic effects toward breast malignancy, was innovatively constructed. Accordingly, engineering this accurate targeting theranostic scheme can be used for efficacious ablation of breast carcinoma. Because Cu and Ca ions can induce ROS generation and cytoplasmic overaccumulation, respectively, here, a Cu–Ca-based nanoplatform was designed by adsorbing indocyanine green (ICG) through the relatively high specific surface area and Arg-Gly-Asp peptide (RGD) decorating by covalent conjugation. Upon the internalization of breast tumor cells, biodegradation was triggered under an intracellular weak acid microenvironment; the released ICG molecules allowed for near-IR (NIR) II fluorescent imaging and photothermal production. Importantly, Cu ions in the nanoplatform guaranteed more efficient Fenton-like reaction-mediated chemodynamic therapy under NIR laser exposure. Meanwhile, the virus-like hollowed Cu–Ca (VhCu-Ca) nanoplatform created an artificial calcium-overloading stress in the cytoplasm. In vitro and in vivo studies have demonstrated that our proposed Cu–Ca-based nanoplatform integrated the advantages of breast tumor targeting, NIR II fluorescent imaging, and efficient ablation via synergistic treatments. Therefore, this multimode nanoplatform developed a facile and versatile strategy for the diagnosis and suppression of breast tumors. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS)-activated prodrugs offer high tumor selectivity due to an abnormal ROS level in tumor cells. However, effective prodrug activation is still limited by inadequate endogenous ROS. Here, we report a ROS-activated nanoparticle consisting of an iron-chelating polyprodrug. Due to its nanostructure, the nanoparticle can achieve effective tumor accumulation via the passive targeting effect. Activated by endogenous ROS in cancer cells, the thioacetal linkers in the nanoparticles will be broken to release cinnamaldehyde and chlorambucil. The former will increase the intracellular ROS level and accelerate drug release; the latter will induce the apoptosis of tumor cells. Therefore, the nanoparticle can realize self-accelerated drug release and a combination of chemotherapy and chemodynamic therapy. This work provides an endogenous ROS-activated self-accelerated drug release strategy to promote the selectivity and efficiency of drug delivery, enhancing cancer treatment. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) generating hydroxyl radicals (•OH) by utilizing metal ions reacting with hydrogen peroxide (H2O2) is a highly encouraging strategy for cancer treatment. However, highly expressed GSH in tumor cells severely limits the efficacy of CDT, and CDT alone is also not sufficient to produce excellent antitumor efficiency. Herein, a dual GSH depletion nanosystem (MnO2@PDA@PEG@DOX) was designed and synthesized to achieve synergistic cancer treatment under ultrasound (US) irritation. To achieve an acidic response, dopamine (DA) was loaded onto manganese dioxide, and the water solubility and stability were greatly improved after PEG modification; finally, the loading of doxorubicin (DOX) achieved the combinational therapy. When the nanoparticles arrived at the tumor site, the acidic and high expression of GSH in the tumor microenvironment prompted the degrading of the nanosystem, followed by the release of MnO2 and DOX. The released MnO2 can react with intracellular GSH to produce Mn2+, which realizes chemodynamic therapy by catalyzing H2O2 to generate highly toxic hydroxyl radicals (•OH) at the tumor site; also, the depletion of GSH will significantly promote the level of •OH, improving the efficiency of CDT simultaneously. Moreover, the release of DOX could be boosted by US irradiation, thus enhancing the effect of chemotherapy on DOX and achieving sonodynamic therapy (SDT). Therefore, strategies to enhance CDT efficiency by dual GSH depletion and combining chemotherapy and sonodynamic therapy modalities can provide more ideas and approaches for combination therapy in cancer treatment. [ABSTRACT FROM AUTHOR]

Artesunate (Art) with a unique peroxy-bridging bond can react with a ferrous ion and produce excess carbon-centered radicals, which cause irreversible damage to tumor cells. However, the antitumor effect of artesunate still faces challenges due to its poor water solubility and insufficient amount of ferrous ions in tumor cells. Herein, we constructed artesunate coordinated zeolite imidazole framework nanoplatforms (Art/ZIF NPs) coated with ferric ion-rutin network (Ru–Fe@Art/ZIF NPs) for synergy therapy. In virtue of zinc-ion-mediated coordination, Art was efficiently loaded into ZIF-8 NPs (loading capacity and rate are 29.58 and 30.73%) and responsively released under an acidic environment. Meanwhile, the introduction of rutin (a type of plant flavonoid) not only enabled tumor targeting via GLUT receptors but also reduced Fe3+ to Fe2+ under acidic conditions. Subsequently, these ferrous ions loading with Art enhance the tumor killing effect via radical-dependent cell cycle arrest. This "core–shell" autocatalytic nanoplatform provides a novel strategy for developing Art-based chemodynamic therapy. [ABSTRACT FROM AUTHOR]

In tumor therapy, tactics for producing reactive oxygen species (ROS) are already being employed to disrupt the balance of redox equilibrium in cells and cause cell death. Among these, chemodynamic therapy (CDT) is an ingenious means to produce ROS via the Fenton reaction. The insufficiency in the tumor site or lability of in vivo administration of hydrogen peroxide has posed significant obstacles to the applications of CDT. Herein, we report docosahexaenoic acid hydroperoxide (D-OOH)-rich-cytomembrane-coated magnetic nanoparticles (MNP@D-OOH) for hydrogen-peroxide-independent CDT. D-OOH is facile to incorporate into the cytomembrane for efficient administration in vivo with little risk of leakage or alteration. In the tumor acid microenvironment, the MNPs decompose into Fe2+, which can react with D-OOH to produce ROS just like Fenton reaction. This study offers beneficial insights for the clinical transformation of CDT. [ABSTRACT FROM AUTHOR]

The combination of photothermal and chemodynamic therapy (PTT/CDT) has promising anticancer effect. Nonetheless, the large-scale preparation of multifunctional nanotherapeutics with good water-solubility and biocompatibility using simple methods remains a major challenge. Herein, we prepared multifunctional nanoparticles (Fe–Ba NPs) by combining Fe3+ with baicalin via a simple coordination assisted self-assembly method, as the carbonyl and phenolic hydroxyl groups in baicalin have strong coordination interaction with Fe3+. The obtained NPs exhibit a broad absorption spectrum extending to near-infrared region and have an excellent photothermal conversion efficiency of 91.1 %. In addition, glutathione (GSH), which is highly expressed in tumor, can reduce Fe3+ in Fe–Ba NPs to Fe2+. On the one hand, Fe2+ can further react with H2O2 to generate hydroxy radical, resulting in CDT. Conversely, depletion of GSH in tumors can disrupt redox homeostasis and upregulate CDT-mediated oxidative damage, leading to enhanced CDT effect. By integrating PTT and CDT, Fe–Ba NPs can greatly improve the therapeutic efficacy. This research introduces a strategy for the design and synthesis of multifunctional nanotherapeutic reagents. [ABSTRACT FROM AUTHOR]

Multifunctional nanomaterials have become a promising nanoplatform for anticancer treatment with tumor specific activation. Here, a cancer cell-activated nanocomposite Cu/ZIF-8@MPN@DOX@F127 (CZMDF) was constructed with a metal phenolic network (MPN)-modified Cu/ZIF-8 and loaded with doxorubicin (DOX). CZMDF was degraded to release tannic acid (TA), Fe3+, Cu2+, and DOX in cancer cells. Benefiting from the reducibility of TA, Fe3+ was converted to Fe2+, which could react with endogenous H2O2 to produce a highly toxic hydroxyl radical (•OH) by the Fenton reaction. The Fenton reaction-mediated chemodynamic therapy (CDT) was promoted by the accelerated Fe3+/Fe2+ conversion, which was also enhanced with a Cu2+-based Fenton-like reaction. In addition, endogenous glutathione (GSH) could reduce Fe3+ and Cu2+ to Fe2+ and Cu+, which led to further enhancement of CDT performance. DOX acted as a traditional drug to realize chemotherapy. Furthermore, the heat from MPN after near-infrared irradiation (NIR) could be applied to realize photothermal therapy (PTT). The multifunctional nanocomposite was designed to achieve synergistic tumor treatment with CDT/chemotherapy/PTT. In vitro experiments showed that the CZMDF caused about 70% of cell apoptosis, and the tumor growth in mice was also inhibited in vivo study. This multifunctional nanomaterial enriches the nanocatalyst types for synergistic tumor therapy, providing a nanoplatform for potential clinical transitions. [ABSTRACT FROM AUTHOR]

Multimode therapeutic nanoagents are an urgent need for tumor treatment to surmount major challenges in single-mode antitumor applications. To counter this, we prepared an "all-in-one" therapeutic platform based on near-infrared (NIR)-activatable PEGylation hollow copper selenide nanoparticles (h-CuSe-PEG NPs). The obtained h-CuSe-PEG NPs exhibit an excellent photothermal conversion efficiency of 54.66% to perform photothermal therapy (PTT). The cavity of h-CuSe-PEG NPs could be loaded with the anticarcinogen doxorubicin (DOX) to achieve chemotherapy for tumors. Moreover, h-CuSe-PEG NPs could deplete the overexpressed glutathione (GSH) as well as generate ·OH due to the endogenous H2O2 in the tumor cells to execute chemodynamic therapy (CDT). Additionally, the drug release, the GSH-depletion, and the ·OH production could be further enhanced due to the in situ hyperthermia produced by PTT under the NIR irradiation. It follows that a satisfactory in vitro and in vivo therapeutic effect is acquired. Hence, the NIR-activatable h-CuSe-based nanoplatform for synergistic photoenhanced CDT/PTT/chemotherapy is promising in tumor treatment. [ABSTRACT FROM AUTHOR]

Glucose oxidase (GOx) is a natural biological oxidoreductase. Due to its molecular fragility and low operational stability, its enzymatic activity is inevitably inhibited during the immobilization process. To address this issue, herein, GOx is rationally decorated onto iron-based MIL-53-(Fe) metal–organic framework (MOF) nanomaterials with peroxidase-mimic activity by one-step biomimetic mineralization and then coated with polyvinylpyrrolidone (PVP) to construct the GOx@MIL-53-(Fe)@PVP (GMP) cascade catalytic nanosystem. The decorated GOx displays the enhanced catalytic activity for highly effective oxidation of glucose to gluconic acid and H2O2, and the latter is immediately converted into the hydroxyl radical (·OH) by MIL-53-(Fe) under acidic conditions mediated by the produced gluconic acid, thereby achieving chemodynamic therapy (CDT). The results show that GMP has a good cascade catalytic activity and ·OH-generating ability. The antibacterial efficiencies of GMP are determined to be 99.7% for Staphylococcus aureus and 99.8% for Escherichia coli. When GMP is applied to the bacteria-infected wounds of mice, it can effectively eliminate bacteria in the infection sites, accelerate wound healing, and cause negligible damage to the healthy tissues and major organs. The developed GMP possesses satisfactory antibacterial effects in vitro and in vivo, demonstrating great potential in treating bacterial infections. [ABSTRACT FROM AUTHOR]

Simultaneous photodynamic/photothermal therapy (PDT/PTT) is a combination cancer treatment that combines the principles of both PDT and PTT to achieve an effective and comprehensive attack on cancer cells. However, both approaches require an external light source to generate reactive oxygen species (ROS) and thermal heat, which could potentially hinder the therapeutic efficacy due to the low tissue penetration of light in vivo. Chemodynamic therapy (CDT) is a type of therapy that uses the ROS generated by the chemical reaction between a prodrug and a catalyst to kill cancer cells. We developed a combination therapy of three modalities (PTT/PDT/CDT) using the metal-organic framework (MOF). The Cu2+-doped MOF PCN-224 nanostructures modified with platinum (Pt) cluster and folic acid (FA) provided excellent tumor targeting, photothermal conversion ability, and ROS generated by the Pt cluster and Cu2+ under 650 nm light irradiation. Moreover, this multimodel nanocomposite had an extremely low dark toxicity but excellent phototoxicity under the combination laser irradiation at 650 nm, both in vitro and in vivo. Therefore, our prepared folic acid-conjugated PCN-224/Pt/Cu2+ (FA-PPC) nanosphere could be applied as a very promising multimodal phototherapeutic agent for enhanced cancer therapy in future clinical applications. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) and photothermal therapy (PTT) have been widely studied as treatment alternatives to anbiotics to avoid the occurrence of bacterial resistance because of their negligible bacterial resistance and high antibacterial efficiencies. Herein, we developed an infection microenvironment-responsive nanogel (STF) to successfully achieve a PTT synergized CDT for bacterial infection. Through a one-step/pot method, STF nanotherapeutics consisting of Fe3+/sodium alginate (SA) based nanogels and Fe3+/tannic acid (TA) based metal–phenolic networks (MPNs) were conveniently prepared by the coordination-triggered simultaneous self-assembly of SA, TA, and Fe3+ ions. Afterward, their photothermal and catalytic performances were intensively investigated. Moreover, the sterilization effect of the STF nanogel was evaluated through in vitro and in vivo bactericidal assays. The STF nanogel exhibited a photothermal enhanced peroxidase-like activity because of the good photothermal effect of MPNs. In addition, its Fenton activity was further accelerated by an extra amount of Fe2+ derived from the degradation of Fe3+-chelating agents (SA) and reduction of TA. Together, the STF nanogel possessed a photothermal/Fe2+ dual-augmented catalytic property. In vitro and in vivo antibacterial assays proved its satisfactory bactericidal efficiency owing to PTT/Fe2+ dual-enhanced CDT. Our research findings suggested that the developed intelligent bactericidal nanogel has great potential to be used as an antibiotic alternative to avoid bacterial resistance in future clinical treatments. [ABSTRACT FROM AUTHOR]

The abnormal blood vessels in tumor sites, causing poor tumor perfusion and hypoxia environment, restrict the chemodynamic therapy (CDT) potency significantly. To attain the synergistic therapy of tumor vascular normalization with CDT, herein, we constructed a dual-functional nanocatalyst with a simple structure, cuprous oxide by dextran (Cu2O@Dex), to restore proper tumor perfusion and tumor oxygenation. The in vitro experiment outcomes illustrated that Cu2O@Dex hardly releases Cu (Cu+/2+) under neutral conditions, which avoids unnecessary catalytic reaction in blood circulation. Under the weak acidic condition (pH 6.5), Cu2O@Dex begins to release Cu (Cu+/2+), catalyzing the nitric oxide (NO) generation for vascular normalization. Also, Cu2O@Dex further releases a large amount of Cu (Cu+/2+) under more acidic intratumor cells (pH 5.5), fast catalyzing the hydroxyl radical (·OH) generation for CDT. The in vivo experiment observations verified that Cu2O@Dex could improve tumor perfusion significantly 3 h post injection, which lasted for more than 144 h. The effective perfusion (Hoechst 33342+) area in the Cu2O@Dex group was 3.8-fold higher than that in the phosphate buffer saline (PBS) group after 48 h of injection, confirming the effectiveness of Cu2O@Dex to induce vascular normalization. Noticeably, tumor vascular normalization further enhanced the therapeutic effect of CDT through delivery of H2O2 generator juglone (JUG) more smoothly. The antitumor efficacy of Cu2O@Dex plus JUG was 86.5% with no obvious toxicity. Overall, our design achieved the dual-catalytic effects integrated in one simple nanostructure for tumor vascular normalization-enhanced CDT. [ABSTRACT FROM AUTHOR]

Drug-resistant bacterial infections pose a significant threat to global public health. Furthermore, the formation of biofilms makes traditional antibiotic treatments significantly less effective in killing multidrug-resistant (MDR) bacteria. In this work, we prepared a molybdenum disulfide (MoS2) nanosphere-based nanocomposite that utilized both photothermal therapy (PTT) and chemodynamic therapy (CDT) for effectively eradicating biofilms. A layer of manganese dioxide (MnO2) was adsorbed onto the surface of the MoS2 nanospheres by redox and electrostatic adsorption methods, and the resulting MoS2/MnO2 were loaded with 2,2′-azobis-[2-(2-imidazolin-2-yl)-propane]-dihydrochloride (AIPH) to form the MoS2/MnO2-AIPH nanocomposite (MMA). The microenvironment of biofilms is slightly acidic, lacks oxygen, and has a high concentration of glutathione (GSH). The MnO2 was capable of reacting with GSH to deplete it while also generating •OH radicals for CDT. In the presence of NIR light (808 nm), the temperature increase brought about by PTT further enhanced the CDT efficacy synergistically. The results showed that the photothermal conversion efficiency of the MMA was 40.5% at a concentration of 100 μg/mL, and the biofilm eradication rate of both MDR Escherichia coli and MDR Staphylococcus aureus was above 90%. The high bacterial inhibition rate (above 96%), as well as the excellent biosafety and biocompatibility of the MMA nanocomposite enabled it to effectively promote wound healing, which has significant implications in treating bacterial infections and promoting wound healing in clinical settings. [ABSTRACT FROM AUTHOR]

Infection microenvironment-mediated chemodynamic therapy (CDT) is an attractive way for the therapy of bacterial infection. However, therapeutic agents which can obtain real-time and in situ pathological information imaging signals during CDT are rare. Thus, it is an urgent need to explore antibacterial agents with both bacterial elimination and treatment process monitoring ability. Herein, we report an activatable antimicrobial nanoplatform with both ultralow-background persistent luminescent (PL) "turn-on" imaging and therapeutic capability. Chitosan (CS) is used as a linker to immobilize copper ions on the surface of persistent luminescent nanoparticles (PLNPs) to fabricate PLNPs–CS–Cu2+. The PL emission of PLNPs is quenched by Cu2+ under physiological conditions but recovered due to the conversion of Cu2+ into Cu+ by high glutathione (GSH) levels at the infection site. The produced Cu+ catalyzes H2O2 to generate hydroxyl radicals (•OH) for bacterial killing through oxidative stress. Also, the depletion of GSH amplifies the oxidative stress and enhances the therapy efficacy. The as-prepared antibacterial nanoplatform is promising for highly sensitive persistent luminescent imaging and simultaneous treatment of bacterial infection. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1α (HIF-1α)-dependent liver-metastasis-related factor expression mediates breast cancer liver invasion and metastasis, so downregulation of HIF-1α is of great significance for breast cancer treatment and liver metastasis prevention. Herein, UCNPs@mSiO2@Ce6&α-ketoglutarate&GOx@mMnO2@HA (UCAGMH), a smart drug-delivery nanoplatform of about 60 nm size, was prepared for both breast cancer treatment and liver metastasis prevention. The MnO2 was rapidly degraded by acidic pH to produce large amounts of Mn2+ and O2. Mn2+ acts as a contrast agent for magnetic resonance imaging (MRI) and an ideal Fenton-like agent, while O2 promotes photodynamic therapy (PDT) by alleviating hypoxia and promoting the oxidation of intratumoral glucose (Glu) by glucose oxidase (GOx) for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, H2O2 and glucuronic acid were generated, which further amplifies the chemodynamic therapy (CDT) effect. Moreover, O2 and α-ketoglutarate could inhibit angiogenesis by promoting the production of proline hydroxylase (PHD), which accelerated the degradation of hypoxia-inducible factor-1α (HIF-1α), thus regulating angiogenesis-related factors and liver-metastasis-related factors. Angiogenesis inhibition and nutrient depletion at the tumor site can achieve ST, which is a promising strategy for cancer treatment, especially for suppressing the metastasis of tumor cells. The nanoparticles could achieve multimodal imaging (i.e., Ce6-endowed fluorescence imaging, UCNPs-provided computed tomography, and Mn2+-enabled MRI) to guide disease progression and therapeutic efficacy. This cascade bioreactor has the ability to modulate the tumor microenvironment, opening up opportunities to inhibit patterns of breast cancer invasion and metastasis through changes in the HIF-1α downregulated signaling pathways and synergies with multiple therapies. [ABSTRACT FROM AUTHOR]

Ion interference therapy (IIT) is a promising cancer treatment strategy that can reverse ion distribution via bioactive nanomaterials so as to interfere with or hinder the physiological processes such as metabolism and proliferation of tumor cells. In this study, a dendritic Cu2+-doped calcium silicate nanosphere (Ca2SiO4) loaded with ruthenium red (RuR) and disulfiram (DSF) (RD-CCP) was constructed for self-enhanced chemodynamic therapy and IIT of tumors through the combination of Cu and Ca. Under the slightly acidic environment of the tumor, dendritic RD-CCP nanospheres (NPs) rapidly collapsed, and a toxic dithiocarbamate–Cu complex was generated in situ through the chelation reaction between DSF and the co-released Cu2+ ions. ROS accumulation was promoted by Fenton-like reaction between the Cu+ ions and the high level of H2O2 and glutathione. In addition, Ca2+-overload was promoted by the combination of the input of exogenous Ca2+ and the participation of RuR, which can inhibit the Ca2+ transport channel (MCU and SERCA), therefore promoting mitochondrial damage and enhancing oxidative stress in tumor cells. Furthermore, calcium transport channel imbalance caused by oxidative stress can promote tumor calcification and necrosis. In conclusion, dendritic RD-CCP NPs can simultaneously induce a Fenton-like response and a calcium-related signal imbalance at the tumor site through the double interference of Cu2+ and Ca2+, eventually leading to rapid tumor apoptosis, which has great application potential in the clinical application of tumor therapy. [ABSTRACT FROM AUTHOR]

A combination of therapeutic modalities in a single nanostructure is crucial for a successful cancer treatment. Synergistic photothermal therapy (PTT) can enhance the effects of chemodynamic therapy (CDT) and chemotherapy, which could intensify the therapeutic efficacy to induce cancer cell apoptosis. In this study, Fe and Mn on a zeolitic imidazolate framework (ZIF-8) (Fe/Mn-ZIF-8; FMZ) were synthesized through ion deposition. Furthermore, bismuth sulfide nanorods (Bi 2 S 3 NRs; BS NRs) were synthesized via a hydrothermal process and coated onto FMZ to generate the core-shell structure of the Bi 2 S 3 @FMZ nanoparticles (B@FMZ). Next, methotrexate (MTX) was loaded effectively onto the porous surface of ZIF-8 to form the B@FMZ/MTX nanoparticles. The Fenton-like reaction catalyzes Fe 2+ /Mn 2+ ions by decomposing H 2 O 2 in the tumor microenvironment, resulting in the formation of toxic hydroxyl radicals (·OH), which promotes the CDT effect of killing cancer cells. Furthermore, under 808 nm laser irradiation, these B@FMZ nanoparticles showed a strong PTT effect, owing to the presence of intense BS NRs as a photothermal agent. The B@FMZ nanoparticles exhibited a prominent drug release efficiency of 87.25% at pH 5.5 under near-infrared laser irradiation due to the PTT effect can promote the drug delivery performance. The B@FMZ nanoparticles were subjected to dual-modal imaging, guided magnetic resonance imaging, and X-ray computed tomography imaging. Both in vitro and in vivo results suggested that the B@FMZ/MTX nanoparticles exhibited enhanced antitumor effects through the combined therapeutic effects of PTT, CDT, and chemotherapy. Therefore, these nanoparticles exhibit good biocompatibility and are promising candidates for cancer treatment.

Integrating chemodynamic therapy (CDT) with Ca 2+ overload offers a potent strategy for enhancing cancer immunotherapy. However, the effectiveness of this approach is significantly constrained by the scarce availability of H 2 O 2 in solid tumors. Here, we engineered a nanoplatform based on CaO 2 nanoparticles (NPs) capable of encapsulating curcumin (CUR) and self-supplying H 2 O 2 for synergistic CDT-augmented antitumor immunotherapy (CaO 2 @CUR@ZIF-Cu, denoted as CCZC). In the acidic tumor microenvironment, CCZC disintegrated to release CUR and copper(II) ions (Cu 2 + ), revealing the core CaO 2 NPs. CDT was amplified by escalating hydroxyl radical ( • OH) production through a Fenton-like reaction mediated by H 2 O 2 from the hydrolysis of CaO 2 NPs. Ca 2+ sourced from CaO 2 NPs and CUR, an initiator of Ca 2+ overload, induced Ca 2+ overload in tumor cells, thereby promoting apoptosis. Subsequently, apoptotic tumor cells released tumor-associated antigens and pro-inflammatory cytokines, triggering adaptive immune responses and enhancing antitumor immunotherapy effects. In vivo experiments demonstrated that the intratumoral administration of CCZC displayed significant inhibitory effects, with an inhibition rate of up to 78% on B16-OVA-tumor-bearing mice compared to untreated. Moreover, an elevated proportion of mature dendritic cells were observed in the tumor-draining lymph nodes, along with an increase in cytotoxic T lymphocytes in the spleen. These findings suggest that our engineered nanoplatform effectively curtailed tumor growth via enhanced cancer immunotherapy by synergizing Ca 2+ overload and CDT, proposing a novel strategy for synergistic cancer treatment.

Despite the advancements in cancer therapy, delivering active pharmaceutical ingredients (APIs) using nanoparticles remains challenging due to the failed conveyance of the required drug payload, poor targeting ability, and poor biodistribution, hampering their clinical translation. Recently, the appropriate design of materials with intrinsic therapeutic functionalities has garnered enormous interest in the development of various intelligent therapeutic nanoplatforms. In this study, we demonstrate the fabrication of transition metal (molybdenum, Mo)-doped manganese dioxide (MnO 2 ) nanoarchitectures, exhibiting diagnostic (magnetic resonance imaging, MRI) and therapeutic (chemodynamic therapy, CDT) functionalities. The facile hydrothermal approach-assisted Mo-doped MnO 2 flower-like nanostructures offered tailorable morphologies in altered dimensions, precise therapeutic effects, exceptional biocompatibility, and biodegradability in the tumor microenvironment. The resultant defects due to doped Mo species exhibited peroxidase and oxidase activities, improving glutathione (GSH) oxidation. The two sets of variable valence metal ion pairs (Mn 2+ /Mn 4+ and Mo 5+ /Mo 6+ ) and their interplay could substantially improve the Fenton-like reaction and generate toxic hydroxyl radicals ( • OH), thus achieving CDT-assisted antitumor effects. As inherent T1-MRI agents, these MnO 2 nanoparticles displayed excellent MRI efficacy in vitro . Together, we believe that these conformational Mo-doped MnO 2 nanoarchitectures with two pairs of variable valence states could potentiate drugless therapy in pharmaceutics.

Chemodynamic therapy (CDT) can induce cancer cell death through hydroxyl radicals (·OH) generated from Fenton or Fenton-like reactions. Compared with traditional therapies, CDT effectively overcomes inevitable drug resistance and exhibits low side effects. However, clinical application still faces challenges, primarily due to insufficient ·OH generation and the short-lifetime of ·OH in vivo. To address these challenges, we developed a peroxynitrite (ONOO - )-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg), and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier for loading DOX and a source of Cu + for triggering CDT. Upon uptake by cancer cells, the high concentration of glutathione (GSH) reduces MOF-199 to Cu + , which then reacts with H 2 O 2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H 2 O 2 level and thereby promoting a high-efficiency Fenton-like reaction for sufficient ·OH generation. Subsequently, PArg generates abundant NO in response to the tumor microenvironment, leading to a cascade of NO and ·OH for the in situ synthesis of ONOO - . ONOO - is more toxic and has a longer lifetime and diffusion distance than ·OH, resulting in a more effective CDT treatment. To further enhance the in vivo therapeutic effect, we coated DOX@PMOF with a homologous cell membrane to form an active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated the ability to effectively inhibit tumor growth and metastasis while exhibiting good biosafety.

Phototherapy has demonstrated substantial development because in the second near-infrared (NIR-II) window it has a larger tissue penetration and fewer adverse consequences. In this work, a particular kind of NIR-II responsive Fe-doped carbon nanoparticles (FDCNs) is synthesized using a one-pot hydrothermal method for combined photothermal and chemodynamic therapy. The mesoporous nanostructure of FDCN, which has a size distribution that exceeds 225 nm, allows for effective acidification. The iron ions released from these nanoparticles can catalyze the decomposition of hydrogen peroxide (H 2 O 2 ) into hydroxyl radical (•OH) for chemodynamic therapy (CDT). In addition to their CDT utility, FDCN can effectively adsorb and transform 1064 nm light into local heat, achieving a photothermal conversion efficacy (PCE) of 36.3%. This dual functionality not only allows for the direct eradication of cancer cells through photothermal therapy (PTT) but also enhances the chemodynamic reaction, creating a synergistic effect that amplifies the therapeutic outcome. The FDCN has demonstrated remarkable anticancer activity in both cellular and animal tests without incurring major systemic toxicity. This suggests that the compound has great promise for use in clinical cancer therapy.

This study emphasizes the innovative application of FePt and Cu core-shell nanostructures with increased lattice microstrain, coupled with Au single-atom catalysis, in significantly enhancing • OH generation for catalytic tumor therapy. The combination of core-shell with increased lattice microstrain and single-atom structures introduces an unexpected boost in hydroxyl radical ( • OH) production, representing a pivotal advancement in strategies for enhancing reactive oxygen species. The creation of a core-shell structure, FePt@Cu, showcases a synergistic effect in • OH generation that surpasses the combined effects of FePt and Cu individually. Incorporating atomic Au with FePt@Cu/Au further enhances • OH production. Both FePt@Cu and FePt@Cu/Au structures boost the O 2 → H 2 O 2 → • OH reaction pathway and catalyze Fenton-like reactions. This enhancement is underpinned by DFT theoretical calculations revealing a reduced O 2 adsorption energy and energy barrier, facilitated by lattice mismatch and the unique catalytic activity of single-atom Au. Notably, the FePt@Cu/Au structure demonstrates remarkable efficacy in tumor suppression and exhibits biodegradable properties, allowing for rapid excretion from the body. This dual attribute underscores its potential as a highly effective and safe cancer therapeutic agent.

As a kind of reactive oxygen species (ROS)-mediated cancer therapy modality, chemodynamic therapy (CDT) has been extensively explored. However, the insufficient endogenous H2O2 and the intracellular redox homeostasis greatly obstruct the anticancer efficacy. Developing multifunctional nanomedicine which can address these issues is appealing. Herein, 4T1 cancer cell membrane (CM)-coated glutathione (GSH)-responsive biodegradable biomimetic nanoreactor, CaO2@MnO2–DOX@CM, was fabricated for tumor oxidative stress amplification enhanced self-supplying H2O2 chemodynamic therapy and synergistic chemotherapy. Highly expressed GSH in the tumor cells could trigger the biodegradation of CaO2@MnO2–DOX@CM, and the Fenton-like catalyst Mn2+ and chemotherapy drug doxorubicin (DOX) were released. The unprotected CaO2 further reacted with water to generate a large amount of H2O2 and Ca2+. The self-supplying H2O2 not only reacted with Mn2+ to generate hydroxyl radical (•OH) but also sped up the biodegradation of the nanoreactor. Furthermore, the MnO2-mediated GSH depletion and the Ca2+-overloading-induced mitochondria dysfunction could further enhance the CDT efficiency. Thus, the glutathione-responsive biodegradable core–shell nanoparticles achieved MRI-guided synergistic chemo–chemodynamic therapy, showing bright prospect for highly efficient tumor treatment. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT), employing metal ions to transform endogenous H 2 O 2 into lethal hydroxyl radicals ( • OH), has emerged as an effective approach for tumor treatment. Yet, its efficacy is diminished by glutathione (GSH), commonly overexpressed in tumors. Herein, a breakthrough strategy involving extracellular vesicle (EV) mimetic nanovesicles (NVs) encapsulating iron oxide nanoparticles (IONPs) and β-Lapachone (Lapa) was developed to amplify intracellular oxidative stress. The combination, NV-IONP-Lapa, created through a serial extrusion from ovarian epithelial cells showed excellent biocompatibility and leveraged magnetic guidance to enhance endocytosis in ovarian cancer cells, resulting in selective H 2 O 2 generation through Lapa catalysis by NADPH quinone oxidoreductase 1 (NQO1). Meanwhile, the iron released from IONPs ionization under acidic conditions triggered the conversion of H 2 O 2 into • OH by the Fenton reaction. Additionally, the catalysis process of Lapa eliminated GSH in tumor, further amplifying oxidative stress. The designed NV-IONP-Lapa demonstrated exceptional tumor targeting, facilitating MR imaging, and enhanced tumor suppression without significant side effects. This study presents a promising NV-based drug delivery system for exploiting CDT against NQO1-overexpressing tumors by augmenting intratumoral oxidative stress.

Currently, specific cancer-responsive fluorogenic probes with activatable imaging and therapeutic functionalities are in great demand in the accurate diagnostics and efficient therapy of malignancies. Herein, an all-in-one strategy is presented to realize fluorescence (FL) imaging-guided and synergetic chemodynamic-photodynamic cancer therapy by using a multifunctional alkaline phosphatase (ALP)-response aggregation-induced emission (AIE) probe, TPE-APP. By responding to the abnormal expression levels of an ALP biomarker in cancer cells, the phosphate groups on the AIE probe are selectively hydrolyzed, accompanied by in situ formation of strong emissive AIE aggregates for discriminative cancer cell imaging over normal cells and highly active quinone methide species with robust chemodynamic-photodynamic activities. Consequently, the activated AIE probes can efficiently destroy cancer cell membranes and lead to the death of cancer cells within 30 min. A superior efficacy in cancer cell ablation is demonstrated in vitro and in vivo. The cancer-associated biomarker response-derived discriminative FL imaging and synergistic chemodynamic-photodynamic therapy are expected to provide a promising avenue for precise image-guided cancer therapy.

Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OH • ) from hydrogen peroxide (H 2 O 2 ) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH • is easily scavenged by glutathione (GSH) and the intracellular H 2 O 2 level is insufficient in the tumor cells. Herein, we propose the Mn 2+ -menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH • storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H 2 O 2 via redox cycling, and further the cytotoxic OH • burst was induced by Mn 2+ -mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.

Reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) hold great promise for tumor treatment. However, hypoxia, insufficient H 2 O 2 , and overexpressed glutathione (GSH) in the tumor microenvironment (TME) hinder ROS generation significantly. Herein, we reported CaO 2 @Cu-TCPP/CUR with O 2 /H 2 O 2 /Ca 2+ self-supply and GSH depletion for enhanced PDT/CDT and Ca 2+ overload synergistic therapy. CaO 2 nanospheres were first prepared and used as templates for guiding the coordination between the carboxyl of tetra-(4-carboxyphenyl)porphine (TCPP) and Cu 2+ ions as hollow CaO 2 @Cu-TCPP, which facilitated GSH-activated TCPP-based PDT and Cu + -mediated CDT. The hollow structure was then loaded with curcumin (CUR) to form CaO 2 @Cu-TCPP/CUR composites. Cu-TCPP prevented degradation of CaO 2 , while Cu 2+ ions reacted with GSH to deplete GSH, produce Cu + ions, and release TCPP, CaO 2 , and CUR. CaO 2 reacted with H 2 O to generate O 2 , H 2 O 2 , and Ca 2+ to achieve O 2 /H 2 O 2 /Ca 2+ self-supply for TCPP-based PDT, Cu + -mediated CDT, and CUR-enhanced Ca 2+ overload therapy. Thus, this multilevel ROS amplifier enhances synergistic therapy with fewer side effects and drug resistance.

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.

Multimodal tumor therapy with nanotechnology is an effective and integrative strategy to overcome the limitations of therapeutic efficacy and possible side effects associated with monotherapy. However, the construction of multimodal treatment nanoplatforms often involves various functional components, leading to certain challenges, such as time-consuming synthesis processes, low product yield, and inadequate biocompatibility. To address these issues, we have developed a straightforward method for preparing ultrathin Cu 9 S 5 nanosheets (NSs) with surface defects for photothermal/photodynamic/chemodynamic therapy. The ultrathin morphology of the Cu 9 S 5 NSs (with 2-3 nm) not only confers excellent biocompatibility but also enables broad-spectrum absorption with a remarkable photothermal conversion efficiency (58.96%) under 1064 nm laser irradiation. Moreover, due to the presence of a S vacancy, these Cu 9 S 5 NSs exhibit favorable enzyme-like properties, including reactive oxygen species generation and glutathione consumption, particularly under laser irradiation. The efficacy of related tumor therapy and antibacterial treatment is significantly enhanced by the synergistic activation of photothermal/photodynamic/chemodynamic therapy through 1064 nm laser irradiation, as demonstrated by both in vitro and in vivo experiments. This study presents a novel strategy for multimodal tumor therapy with the prepared ultrathin Cu 9 S 5 NSs, which holds promising pathways for photodynamic therapy in the NIR-II region.

Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal-organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu 2+ ) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu 2+ was reduced to Cu + by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (H 2 O 2 ) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy.

Different valence states of copper (Cu) ions are involved in complicated redox reactions in vivo , which are closely related to tumor proliferation and death pathways, such as cuproptosis and chemodynamic therapy (CDT). Cu ion mediated Fenton-like reagents induced tumor cell death which presents compelling attention for the CDT of tumors. However, the superiority of different valence states of Cu ions in the antitumor effect is unknown. In this study, we investigated different valence states of Cu ions in modulating tumor cell death by Cu-chelated cyanine dye against triple-negative breast cancer. The cuprous ion (Cu + ) and copper ion (Cu 2+ ) were chelated with four nitrogen atoms of dipicolylethylenediamine-modified cyanine for the construction of Cu + and Cu 2+ chelated cyanine dyes (denoted as CC1 and CC2, respectively). Upon 660 nm laser irradiation, the CC1 or CC2 can generate reactive oxygen species, which could disrupt the cyanine structure, achieving the rapid release of Cu ions and initiating the Fenton-like reaction for CDT. Compared with Cu 2+ -based Fenton-like reagent, the CC1 with Cu + exhibited a better therapeutic outcome for the tumor due to there being no need for a reduction by glutathione and a shorter route to generate more hydroxyl radicals. Our findings suggest the precision delivery of Cu + could achieve highly efficient antitumor therapy.

To meet the requirements of biomedical applications in the antibacterial realm, it is of great importance to explore nano-antibiotics for wound disinfection that can prevent the development of drug resistance and possess outstanding biocompatibility. Therefore, we attempted to synthesize an atomically dispersed ion (Fe) on phenolic carbon quantum dots (CQDs) combined with an organic photothermal agent (PTA) (Fe@SAC CQDs/PTA) via a hydrothermal/ultrasound method. Fe@SAC CQDs adequately exerted peroxidase-like activity while the PTA presented excellent photothermal conversion capability, which provided enormous potential in antibacterial applications. Based on our work, Fe@SAC CQDs/PTA exhibited excellent eradication of Escherichia coli (>99% inactivation efficiency) and Staphylococcus aureus (>99% inactivation efficiency) based on synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT). Moreover, in vitro experiments demonstrated that Fe@SAC CQDs/PTA could inhibit microbial growth and promote bacterial biofilm destruction. In vivo experiments suggested that Fe@SAC CQDs/PTA-mediated synergistic CDT and PTT exhibited great promotion to wound disinfection and recovery effects. This work indicated that Fe@SAC CQDs/PTA could serve as a broad-spectrum antimicrobial nano-antibiotic, which was simultaneously beneficial for bacterial biofilm eradication, wound disinfection, and wound healing.

In the tumor microenvironment (TME), an efficient Fenton reaction agent could have attractive tumor therapeutic efficacy, which is primarily based on delivering drugs to the tumor accurately and depressing undesirable side effects. Here, a metal–organic framework (MOF), with good biocompatibility and high loading capacity, with encapsulated FePt NPs (FePt-MOF NCs) and face-centered cubic (fcc)-FePt was successfully designed to eradicate cancer cells. The as-prepared multifunctional FePt-MOF NCs serve as a nanotheranostic agent for magnetic resonance/computed tomography (MR/CT) dual-modal imaging based on superparamagnetism and cancer therapy due to the well-known Fenton reactions. The drug nanodelivery system based on MOFs was able to safely deliver on the basis of intravenous administration. Because of its high sensitivity to acidic environments, the FePt-MOF would collapse and further release Fe and Pt ions, which would effectively trigger the Fenton reaction to produce plentiful toxic hydroxyl radicals in the acidic tumor microenvironment. On the one hand, the radicals could result in apoptotic cell death, whereas, on the other hand, they also lure the cumulation of lipid peroxides, causing tumor cell ferroptosis. These results indicated the great potential of the FePt-MOF NCs as a multifunction platform for tumor therapeutic and image applications. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy based on the Fenton reaction has been developed as an extremely promising modality for cancer therapeutics. In this study, a core-shell structure nanoplatform was constructed by a Au nanorod externally encapsulating Ce/Zn-based composites (ACZO). The nanoparticles can catalyze the generation of reactive oxygen species (ROS) under acidic conditions and effectively consume existing glutathione (GSH) to destroy the redox balance within the tumor. Moreover, the decomposition of the nanocomplexes under acidic conditions releases large amounts of zinc ions, leading to zinc overload in cancer cells. The photothermal effect generated by the Au nanorods not only provides photothermal therapy (PTT) but also augments the catalytic reaction and ions action mentioned above. This facile strategy to improve the efficacy of chemodynamic therapy by the photothermal enhancement of catalytic activity and zinc ion release provides a promising perspective for potential tumor treatment.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Cell membrane-coated nanoplatforms for drug delivery have garnered significant attention due to their inherent cellular properties, such as immune evasion and homing abilities, making them a subject of widespread interest. The coating of mixed membranes from different cell types onto the surface of nanoparticles offers a way to harness natural cell functions, enhancing biocompatibility and improving therapeutic efficacy. In this study, we merged membranes from murine-derived 4T1 breast cancer cells with RAW264.7 (RAW) membranes, creating a hybrid biomimetic coating referred to as TRM. Subsequently, we fabricated hybrid TRM-coated Fe 3 O 4 nanoparticles loaded with indocyanine green (ICG) and imiquimod (R837) for combination therapy in breast cancer. Comprehensive characterization of the RIFe@TRM nanoplatform revealed the inherent properties of both cell types. Compared to bare Fe 3 O 4 nanoparticles, RIFe@TRM nanoparticles exhibited remarkable cell-specific self-recognition for 4T1 cells in vitro , leading to significantly prolonged circulation life span and enhanced in vivo targeting capabilities. Furthermore, the biomimetic RIFe@TRM nanoplatform induced tumor necrosis through the Fenton reaction and photothermal effects, while R837 facilitated enhanced uptake of tumor-associated antigens, further activating CD8 + cytotoxic T cells to strengthen antitumor immunotherapy. Hence, RIFe@TRM nanoplatform demonstrated outstanding synergy in chemodynamic/immunotherapy/photothermal therapies, displaying significant inhibition of breast tumor growth. In summary, this study presents a promising biomimetic nanoplatform for effective treatment of breast cancer.

Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to have a serious impact on tumor recurrence and metastasis postresection. Implantation of an in situ hydrogel system postresection has shown to be an effective treatment with great clinical potential. Herein, an injectable zwitterionic hydrogel system was developed for local drug delivery with enhanced immune activation and prevention of tumor recurrence. Driven by electrostatic interactions, poly(sulfobetaine methacrylate) (PSBMA) self-assembles into a hydrogel in saline, achieving low protein adsorption and tunable biodegradability. The chemotherapy drug doxorubicin (DOX) was loaded into copper peroxide nanoparticles (CuO 2 /DOX), which were coated with macrophage membranes to form tumor-targeting nanoparticles (M/CuO 2 /DOX). Next, M/CuO 2 /DOX and the stimulator of interferon genes (STING) agonist 2',3'-cGAMP were coloaded into PSBMA hydrogel (Gel@M/CuO 2 /DOX/STING). The hydrophilic STING agonist was first released by diffusion from hydrogel to activate the STING pathway and upregulate interferon (IFN) signaling related genes, remodeling the immunosuppressive TME. Then, M/CuO 2 /DOX targeted the residual tumor cells, combining with DOX-induced DNA damage, immunogenic tumor cell death, and copper death. Hence, this work combines chemodynamic therapy with STING pathway activation in TME, encouraging residual tumor cell death, promoting the maturation of dendritic cells, enhancing tumor-specific CD8 + T cell infiltration, and preventing postoperative recurrence and metastasis.

Chemodynamic therapy (CDT) has emerged as a promising approach to cancer treatment, which can break the intracellular redox state balance and result in severe oxidative damage to biomolecules and organelles with the advantages of being less dependent on external stimulation, having deep tissue-healing abilities, and being resistant to drug resistance. There is considerable interest in developing CDT drugs with high efficiency and low toxicity. In this study, a new guanidinium-based biological metal covalent organic framework (Bio-MCOF), GZHMU-1@Mo, is rationally designed and synthesized as a multifunctional nanocatalyst in tumor cells for enhanced CDT. The DFT calculation and experimental results showed that due to the ability of MoO 4 2- ion to promote electron transfer and increase the redox active site, Cu 3 clusters and MoO 4 2- ions in GZHMU-1@Mo can synergistically catalyze the production of reactive oxygen species (ROS) from oxygen and H 2 O 2 in tumor cells, as well as degrade intracellular reducing substances, GSH and NADH, so as to disrupt the redox balance in tumor cells. Moreover, GZHMU-1@Mo exhibits a potent killing effect on tumor cells under both normal oxygen and anaerobic conditions. Further in vitro and in vivo antiproliferation studies revealed that the GZHMU-1@Mo nanoagent displays a remarkable antiproliferation effect and effectively inhibits tumor growth. Taken together, our study provides an insightful reference benchmark for the rational design of Bio-MCOF-based nanoagents with efficient CDT.

Chemodynamic therapy based on the Fenton-like catalysis ability of Fe 3 O 4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe 3 O 4 @HfO 2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe 3 O 4 and a radiosensitizer HfO 2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO 2 -Fe 3 O 4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.

Chemodynamic therapy (CDT) has witnessed significant advancements in recent years due to its specific properties. Its association with photodynamic therapy (PDT) has also garnered increased attention due to its mutually reinforcing effects. However, achieving further enhancement of the CDT/PDT efficacy remains a major challenge. In this study, we have developed an integrated nanosystem comprising a Fenton catalyst and multifunctional photosensitizers to achieve triply enhanced CDT/PDT through photothermal effects, H 2 O 2 elevation, and GSH consumption. We prepared nano-ZIF-8 vesicles as carriers to encapsulate ferrocene-(phenylboronic acid pinacol ester) conjugates (Fc-BE) and photosensitizers IR825. Subsequently, cinnamaldehyde-modified hyaluronic acid (HA-CA) was coated onto ZIF-8 through metal coordination interactions, resulting in the formation of active targeting nanoparticles (NPs@Fc-BE&IR825). Upon cellular internalization mediated by CD44 receptors, HA-CA elevated H 2 O 2 levels, while released Fc-BE consumed GSH and catalyzed H 2 O 2 to generate highly cytotoxic hydroxyl radicals (·OH). Furthermore, NIR irradiation led to increased ·OH production and the generation of singlet oxygen ( 1 O 2 ), accompanied by a greater GSH consumption. This accelerated and strengthened amplification of oxidative stress can be harnessed to develop highly effective CDT/PDT nanoagents.

Even though great progress has been achieved in mimicking natural enzyme engineering, few artificial enzymes with efficient catalytic performance and multifunction have been reported. In this study, novel manganese-iron dual single-atom catalysts (Mn/Fe SACs) were synthesized via a hydrothermal/pyrolysis recipe. Iron atoms inside the Mn/Fe SACs adequately exerted the peroxidase (POD)-like activity, its Michaelis-Menten constant, and maximum initial velocity superior to the horseradish peroxidase. Manganese atoms sufficiently catalyzed the H 2 O 2 to generate oxygen (O 2 ), which alleviated the challenge of the continued lack of O 2 in the infected wound. In addition, Mn/Fe SACs possess a glutathione oxidase-like activity that further enhanced POD-like activity in the therapeutic process. The antibacterial rates of Mn/Fe SACs were 95 and 94.5% for Escherichia coli and Staphylococcus aureus , respectively. In vitro anti-inflammatory experiments demonstrated that Mn/Fe SACs could regulate the polarization of macrophages into the anti-inflammatory M2 subtype. In vivo wound healing experiments suggested that the combination therapy of Mn/Fe SACs and chemodynamic therapy presented a great promotion of the recovery rate. Moreover, the O 2 generated by the catalase-like process contributed to the catalysts permeating the interior of the infected wounds and achieved preferable abscess elimination ability. This work revealed the potential of Mn/Fe SACs as broad-spectrum antimicrobial materials, which provided a novel strategy for treating infected and abscess wounds.

Chemodynamic therapy (CDT) is a highly tumor-specific treatment, while its efficacy is compromised by the intratumoral Fenton reaction efficiency, which is determined by the following reaction factors, including the availability of Fenton ions (e.g., Fe 2+ ), the amount of H 2 O 2 , and the degree of acidity. Synchronous optimization of these factors is a big challenge for efficient CDT. Herein, a strategy of comprehensively optimizing Fenton reaction factors was developed for traceable multistage augmented CDT by charge-reversal theranostics. The customized pH-responsive poly(ethylene)glycol-poly(β-amino esters) (PEG-PAE) micelle (PM) was prepared as the carrier. Glucose oxidase (GOx), Fe 2+ , and pH-responsive second near-infrared (NIR-II) LET-1052 probe were coloaded by PM to obtain the final theranostics. The activity of metastable Fe 2+ remained by the unsaturated coordination with PEG-PAE. Then tumor accumulation and exposure of Fe 2+ were achieved by charge-reversal cationization of PEG-PAE, which was further enhanced by a GOx catalysis-triggered pH decrease. Together with the abundant H 2 O 2 generation and pH decrease through GOx catalysis, the limiting factors of the Fenton reaction were comprehensively optimized, achieving the enhanced CDT both in vitro and in vivo . These findings provide a strategy for comprehensively optimizing intratumoral Fenton reaction factors to overcome the intrinsic drawbacks of current CDT.

Nanozymes have brought enormous opportunities for disease theranostics. Here, a self-enhanced catalytic nanocrystal based on a bismuth-manganese core-shell nanoflower containing glucose oxide (GOx), termed BDS-GOx@MnO x , was designed for 4T1 tumor theranostics in vitro and in vivo . The BDS-GOx@MnO x nanozymes enable enhanced starvation treatment (ST) and chemotherapy (CDT) with high efficacy and exhibit sensitive tumor microenvironment (TME) responsive character for tumor therapy as well as for tumor-enhanced computer tomography (CT) and magnetic resonance (MR) diagnostic imaging. The characters and mechanism of the BDS-GOx@MnO x nanozymes have also been systematically studied and revealed.

The development of tumor microenvironment (TME)-activated nanoassemblies which can produce a photoacoustic (PA) signal and enhance the H 2 O 2 level is critical to achieve accurate diagnosis and highly efficient chemodynamic therapy (CDT). In this study, we developed nanoassemblies consisting of oxygen vacancy titanium dioxide (TiO 2- x ) surface-constructed copper, sulfur-doped mesoporous organosilica and glucose oxidase (TiO 2- x @Cu,S-MONs@GOx, hereafter TMG). We found that highly abundant glutathione (GSH) in the TME nanoassemblies can reduce tetrasulfide bonds and Cu 2+ to sulfur ions and Cu + in the TMG nanoassemblies, respectively, causing the breakage of the tetrasulfide bond and the mesoporous structure collapse, releasing Cu + ions and TiO 2- x nanoparticles, and producing hydrogen sulfide gas, thereby achieving synergistic multimodal tumor treatment through TME-activated NIR-II PA imaging and photothermal-enhanced gas starvation-primed CDT. Therefore, the TMG nanoassemblies form a smart nanoplatform that can serve as an excellent tumor diagnosis-treatment agent by playing an important role in imaging-guided precision diagnosis of cancer and efficient targeting treatment.

The advent of enzyme-facilitated cascade events in which endogenous substrates within the human body are used to generate reactive oxygen species (ROS) has spawned novel cancer treatment possibilities. In this study, a supramolecular cascade catalytic nanozyme system was successfully developed, exhibiting photothermal-enhanced multienzyme cascade catalytic and glutathione (GSH) depletion activities and ultimately triggering the apoptosis-ferroptosis synergistic tumor therapy. The nanozyme system was fabricated using β-cyclodextrin-functionalized polydopamine (PDA) as the substrate, which was then entangled with polyoxometalate (POM) via electrostatic forces and assembled with adamantane-grafted hyaluronic acid and glucose oxidase (GOx) via host-guest supramolecular interaction for tumor targeting and GOx loading. The catalytic function of GOx facilitates the conversion of glucose to H 2 O 2 and gluconic acid. In turn, this process affirms the propitious generation of hydroxyl radical ( • OH) through the POM-mediated cascade catalysis. Additionally, the POM species actively deplete the intracellular GSH pool, initiating a cascade catalytic tumor therapy. In addition, the PDA-POM-mediated photothermal hyperthermia boosted the cascade catalytic effect and increased ROS production. This confers considerable promise for photothermal therapy (PTT)/nanocatalytic cancer therapy on supramolecular nanozyme systems. The in vitro and in vivo antitumor efficacy studies demonstrated that the supramolecular cascade catalytic nanozyme system was effective at reducing tumor development while maintaining an acceptable level of biocompatibility. Henceforth, this study is to widen the scope of cascade catalytic nanoenzyme production using supramolecular techniques, as well as endeavor to delineate a prospective pathway for the application of PTT-enhanced nanocatalytic tumor therapy.

Tumor drug resistance has long been a major challenge in medical oncology. Ferroptosis is a form of regulated cell death with promising clinical applications. However, the efficacy of ferroptosis-inducing agents is often limited by endogenous factors when used alone, and thus, synergistic therapy offers a promising strategy to address this issue. In this study, we developed an iron-doped metal-organic framework (MOF), Fe/ZIF-8, loaded with glucose oxidase (Gox), l-arginine (l-arg), and adriamycin hydrochloride (Dox). The folic acid (FA)-targeted ZIF-8 (GLDFe/Z-FA) prepared was shown to be a multifunctional nanoparticle based on endogenous hydrogen peroxide (H 2 O 2 ) and glucose, which trigger adaptive cellular responses in cancer cells. The intracellular glucose level and adenosine-triphosphate (ATP) content decreased, indicating that GLDFe/Z-FA reduced the glucose metabolic rate and induced tumor starvation. And the generated • OH and H 2 O 2 induced reactive oxygen species (ROS) overload to implement chemodynamic therapy (CDT). ROS catalyzed l-arg released from GLDFe/Z-FA to release nitric oxide (NO), which inhibited P-glycoprotein expression, prevented Dox efflux, and accumulated intracellular content of Dox to enhance cytotoxicity. GLDFe/Z-FA also catalyzed glutathione degradation, which further disrupted intracellular redox homeostasis, enhanced CDT, and induced cell death. It was shown to follow the ferroptosis pathway and strongly inhibited tumor proliferation both in vitro and in vivo . These findings demonstrate that GLDFe/Z-FA effectively inhibits tumor proliferation, highlighting its potential as a viable therapeutic approach to suppress cancer progression.

In recent years, microbiota-based tumor immunotherapy has become a hotspot in cancer research. However, the use of microorganisms alone to activate the immune response for antitumor therapy was unsatisfactory. In this study, we biosynthesized gold nanoparticles (AuNPs) and platinum nanoparticles (PtNPs) based on yeast microcapsules to activate the immune response for antitumor treatment in synergy with chemodynamic therapy (CDT) and photothermal therapy (PTT). We generated AuNPs and PtNPs on yeast microcapsules (YAP) and fabricated nanoscale particles (Bre-YAP) by ultrasonic fragmentation and differential centrifugation. Bre-YAP retained the glucan component of yeast as an adjuvant; in the meantime, these two kinds of metal nanoparticles contained were excellent CDT and PTT mediators. By inspection, they could reach a high level of distribution in tumors and tumor-draining lymph nodes (TDLNs). Under the laser irradiation of tumors, this immunological nanomaterial significantly remodeled the microenvironments of tumors and TDLNs. The primary tumors were effectively inhibited or even eradicated, and the overall survival of mice was significantly improved as well. Therefore, yeast microcapsule-based Bre-YAP with immune properties could be used as an effective cancer treatment modality.

The rapid development of nanomedicine has brought hope and confidence to the precise treatment of tumors. However, the efficacy of nanoparticle-mediated therapy is severely limited due to phagocytosis and clearance by macrophages. CD47 is a well-documented ″don't eat me″ signaling molecule that binds to the SIRPα receptor on the macrophage surface, inhibiting the phagocytic behavior of the macrophages. In this study, CD47-overexpressing cancer cell membranes were used to coat hollow copper sulfide nanoparticles. The nanoparticles were shown to have an extended circulatory half-life and to actively target breast cancer, leading to increased accumulation in the tumor tissue. An excellent photothermal therapeutic effect was produced by near-infrared laser irradiation. At the same time, β-lapachone within the nanoparticles generated large amounts of hydrogen peroxide in the tumor environment, which was then catalyzed by the copper sulfide nanozyme to cytotoxic hydroxyl radicals, exerting a chemodynamic therapeutic effect. This engineered biomimetic nanozyme, through the mediation of the ″don't eat me″ signal, achieved both photothermal and chemodynamic precision treatments of breast cancer, creating a new mode of safe and effective tumor treatment.