Chemodynamic Therapy Agents Research Articles

NIR-II laser-mediated photo-Fenton-like reaction via plasmonic Cu9S8 for immunotherapy enhancement

Chemodynamic therapy (CDT) is typically used to modulate the immunogenic tumor microenvironment and extend the benefits of immune checkpoint therapy because of its good tumor selectivity. However, the poor catalytic efficiency of CDT agents means that it often needs to be combined with other enhancement strategies, such as radiotherapy and photothermal therapy with high power density, which can inevitably traumatize normal tissues. To overcome these limitations, a near-infrared (NIR)-II laser-mediated photo-Fenton-like reaction based on a plasmonic self-doped semiconductor was proposed as a mild enhancement strategy to enhance the immune responses. Experimental simulations and results of plasmonic Cu9S8 show that the NIR-II laser can enhance the CDT effect based on the plasmon-driven photoredox chemistry without inducing a photothermal effect. Furthermore, the enhanced CDT effectively induces immunogenic cell death and dendritic cell maturation both in vitro and in vivo. In addition, the antitumor immune response is greatly enhanced by the synergistic effect of the NIR-II laser in enhancing both CDT and anti-PD-L1. This allows for primary tumor elimination and the effective suppression of distant tumors and lung metastases. Our proposed design indicates that the NIR-II photo-Fenton-like reaction based on the plasmonic semiconductor effectively enhances CDT, thus selectively enhancing immunotherapy.

Bacterial microenvironment-responsive dual-channel smart imaging-guided on-demand self-regulated photodynamic/chemodynamic synergistic sterilization and wound healing.

Bacterial infections pose a serious threat to public health. The integration of photodynamic therapy (PDT) and chemodynamic therapy (CDT) has emerged as a promising means to combat bacterial infection. However, most photosensitizers are often in the "always on" activated state and lack bacterial targeting, leading to non-specific damage to normal tissues. Besides, most of the conventional CDT systems are directly complexed with metal ions. The toxicity of excess free metal ions cannot be ignored. Therefore, it is a huge challenge to construct a bacteria-specific activated PDT/CDT synergistic therapy platform to achieve precise sterilization. Herein, we report a bacterial microenvironment-responsive phosphorescence/fluorescence dual-channel smart imaging-guided on-demand self-regulating CDT/PDT theranostic platform for precise sterilization and wound healing. Acid-degradable persistent luminescence nanoparticles were prepared as bacterial microenvironment-responsive phosphorescence imaging units and CDT agents. Piperazine-modified PEG was then introduced as an intelligent targeting and hydrophilic group, which was further bonded with a pH-reversibly-activated fluorescence/PDT-in-one probe to construct the intelligent theranostic platform. The developed platform combines the features of good biocompatibility, prolonged blood circulation, charge-reversed intelligent targetability, dual-channel smart imaging and on-demand self-regulating CDT/PDT effect, holding great potential for precise imaging-guided bacteria-specific synergistic sterilization without side effects.

CeO2 QDs anchored on MnO2 nanoflowers with multiple synergistic effects for amplified tumour therapy

Chemodynamic therapy (CDT) is an emerging tumour-specific therapeutic technology. However, the relatively insufficient catalytic activity of CDT agents in the tumour microenvironment (TME) limits their biomedical application. In addition, severe hypoxia and glutathione (GSH) overexpression in the TME greatly limit the antitumour efficiency of monotherapy. Herein, a cancer cell membrane-camouflaged and ultrasmall CeO2-decorated MnO2 (mMC) composite is developed for amplified CDT, photodynamic therapy (PDT) and photothermal therapy (PTT). Due to the homotypic targeting ability of cancer cell membranes, mMC nanoparticles preferentially accumulate in tumour tissue. In the TME, CeO2 acts as a highly efficient CDT agent to convert endogenous H2O2 to toxic reactive oxygen species (ROS) for killing cancer cells. Meanwhile, MnO2 irradiated with near-infrared (NIR) light displays prominent hyperthermia and ROS generation performance to perform PTT and PDT. Moreover, MnO2 can produce oxygen to ameliorate hypoxia and deplete GSH to relieve the antioxidant capability of tumours, which is beneficial to the simultaneous augmentation of PDT and CDT. Most importantly, the catalytic activity of CeO2 was greatly improved by hyperthermia. Consequently, a significantly enhanced therapeutic efficiency was obtained by the above multiple synergistic effects. This work provides a proof of concept for amplified tumour therapy by synchronously self-supplying oxygen, consuming GSH, and enhancing catalytic activity.

Construction of Novel Nanocomposites (Cu-MOF/GOD@HA) for Chemodynamic Therapy.

The emerging chemodynamic therapy (CDT) has received an extensive attention in recent years. However, the efficiency of CDT is influenced due to the limitation of H2O2 in tumor. In this study, we designed and synthesized a novel core-shell nanostructure, Cu-metal organic framework (Cu-MOF)/glucose oxidase (GOD)@hyaluronic acid (HA) (Cu-MOF/GOD@HA) for the purpose of improving CDT efficacy by increasing H2O2 concentration and cancer cell targeting. In this design, Cu-MOF act as a CDT agent and GOD carrier. Cu(II) in Cu-MOF are reduced to Cu(I) by GSH to obtain Cu(I)-MOF while GSH is depleted. The depletion of GSH reinforces the concentration of H2O2 in tumor to improve the efficiency of CDT. The resultant Cu(I)-MOF catalyze H2O2 to generate hydroxyl radicals (·OH) for CDT. GOD can catalyze glucose (Glu) to supply H2O2 for CDT enhancement. HA act as a targeting molecule to improve the targeting ability of Cu-MOF/GOD@HA to the tumor cells. In addition, after loading with GOD and coating with HA, the proportion of Cu(I) in Cu-MOF/GOD@HA is increased compared with the proportion of Cu(I) in Cu-MOF. This phenomenon may shorten the reactive time from Cu-MOF to Cu(I)-MOF. The CDT enhancement as a result of GOD and HA effects in Cu-MOF/GOD@HA was evidenced by in vitro cell and in vivo animal studies.

A Harmless-Harmful Switchable and Uninterrupted Laccase-Instructed Killer for Activatable Chemodynamic Therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H2 O2 ) into hydroxyl radicals (OH•). Although many studies on H2 O2 supplementation have been conducted to improve the therapeutic effect of CDT, few studies have focused on the application of superoxide radical (O2 -• ) in CDT, which may result in better efficacy. A major concern about O2 -• -mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O2 -• scavenger. Here, a harmless-harmful switchable and uninterrupted laccase (LAC)-instructed killer (HULK) is constructed, which is the first CDT agent accelerated by LAC-instructed O2 -• generation and possesses a harmless-harmful switchable effect because of the photodegradation of the O2 -• scavenger iron-chlorin e6 (FeCe6). LAC-instructed substrate oxidation effectively catalyzes O2 -• production with the help of intracellular reduction, thereby promoting the conversion of Fe3+ to Fe2+ , accelerating the generation of OH•, and inducing tumor cell apoptosis and necrosis. The introduced O2 -• scavenger FeCe6 is quickly photodegraded during irradiation, while LAC-instructed O2 -• generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC-instructed O2 -• generation but also presents new insight into activatable CDT.

Singlet Oxygen Generation in Dark‐Hypoxia by Catalytic Microenvironment‐Tailored Nanoreactors for NIR‐II Fluorescence‐Monitored Chemodynamic Therapy

AbstractSinglet oxygen (1O2) has a potent anticancer effect, but photosensitized generation of1O2is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of1O2‐producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment‐tailored nanoreactor (CMTN), constructed by encapsulating MoO42−catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO42−‐catalyzed generation of1O2from H2O2and protects MoO42−from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H2O2and1O2can freely cross the liposomal membrane, allowing CMTN with a built‐in NIR‐II ratiometric fluorescent1O2sensor to achieve monitored tumor CDT.

Singlet Oxygen Generation in Dark-Hypoxia by Catalytic Microenvironment-Tailored Nanoreactors for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Singlet oxygen (1 O2 ) has a potent anticancer effect, but photosensitized generation of 1 O2 is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of 1 O2 -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO42- catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO42- -catalyzed generation of 1 O2 from H2 O2 and protects MoO42- from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H2 O2 and 1 O2 can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent 1 O2 sensor to achieve monitored tumor CDT.

A Traceable, Sequential Multistage‐Targeting Nanoparticles Combining Chemo/Chemodynamic Therapy for Enhancing Antitumor Efficacy

AbstractAlthough chemodynamic therapy (CDT) can effectively inhibit tumor growth and metastasis, it is challenging to eliminate tumors. Generally, CDT needs to combine with extra therapeutic modes for enhancing antitumor efficacy. Here, novel nanoparticles (BDTLAG NPs) are constructed via self‐assembly of cancer cell targeting prodrug (Bio‐PEG2K‐S‐S‐CPT), organic CDT agents (TPP‐PEG2K‐LND, TPP‐PEG2K‐TOS), pH‐responsive prodrug (PEG2K‐NH‐N‐DOX), T1‐enhanced magnetic resonance imaging contrast agents (Gd‐DTPA‐N16‐16), and anti‐angiogenic drug combrestatinA4 (CA4), realizing chemo(CT)‐chemodynamic combination therapy. The mechanism of BDTLAG NPs for enhancing antitumor efficacy involves: (i) BDTLAG NPs is accumulated in the tumor tissue by passive targeting; (ii) CA4 is released and specifically destroys angiogenesis, and the remaining BDTLG NPs enter the tumor cell via active targeting; (iii) the acid/glutathione (GSH)‐responsive prodrug release and GSH depletion; (iv) TPP‐PEG2K‐LND and TPP‐PEG2K‐TOS are accumulated in the tumor cell mitochondria due to mitochondria‐targeting, and is accompanied by endogenous reactive oxygen species bursts. This current strategy of single NPs that integrates spatiotemporally CT, CDT, GSH depletion, and MR imaging functions reflects the “all in one” concept, which provides a new opportunity for enhancing antitumor efficacy.

Self-Assembly Iron Oxide Nanoclusters for Photothermal-Mediated Synergistic Chemo/Chemodynamic Therapy.

Methods Superparamagnetic iron oxide nanoclusters (SPIOCs) were located within the core, which resulted in high photothermal conversion and outstanding generation of reactive oxygen species (ROS). The shell consisted of a human serum albumin- (HSA-) paclitaxel (PTX) layer, which extended the blood circulation time and ensured the effectiveness of the chemotherapy. Arg-Gly-Asp peptides (RGD) were linked to the naked cysteine moieties in HSA to promote the specific targeting of human glioma U87 cells by αvβ3 integrins. Continuous near-infrared light irradiation triggered and promoted the synergistic chemo/CDT therapy through the photothermal effect. Results Our SPIOCs@HSA-RGD nanoplatform showed well biocompatibility and could target glioma specifically. Photothermal conversion and ROS burst were detected after continuous 808 nm light irradiation, and a significant antitumor effect was achieved. Conclusion Experimental in vitro and in vivo evaluations showed that our photothermal-mediated chemo/CDT therapy could efficiently inhibit tumor growth and is therefore promising for cancer therapy.

Biomineralized DNA nanospheres by metal organic framework for enhanced chemodynamic therapy

Chemodynamic therapy (CDT) has emerged as an innovative treatment strategy for cancer therapy, and yet most of current systems are highly dependent on endogenous H2O2 for hydroxyl radical (OH) generation, leading to limited therapeutic efficacy. Therefore, it is of significant importance to develop CDT agents with efficient H2O2 self-supplying ability for enhanced CDT efficacy. Herein, we report metal organic framework (MOF)-biomineralized DNA nanospheres as CDT agent engineered with tumor-activable cascade reactions for boosting the intracellular H2O2 concentration, thus achieving remarkable antitumor outcome. As a result of tumor acid-induced dissociation of CDT agent, the released Fe2+/Fe3+ triggers Fenton reaction to produce OH and the released GOx enables to catalyze glucose into H2O2, which synergistically elevates the ROS level in tumor cells and induces ferroptosis. By exploitation of tumor acid-activable cascade reactions for supplying sufficient H2O2, our CDT agent achieves prominent therapeutic efficacy in both in vitro and in vivo assays. Our work provides a promising strategy to develop CDT agents for improved CDT efficacy.

Recent progress of chemodynamic therapy-induced combination cancer therapy

Abstract Chemodynamic therapy (CDT) is an emerging cancer treatment strategy that uses CDT agents to convert hydrogen peroxide (H2O2) into the hydroxyl radical ( OH), the most harmful reactive oxygen species (ROS) by the Fenton/Fenton-like reactions, thus inducing cell apoptosis and necrosis. This treatment method has been widely studied because of its minimal invasiveness and high tumor specificity, and has become a popular topic of research. Despite the great potential of CDT in tumor treatment, the clinical conversion of CDT is still facing challenges: 1) the relatively high pH of the tumor sites is not suitable for the occurrence of most Fenton/Fenton-like reactions; 2) the low concentration of endogenous H2O2 at the tumors is not enough to generate continuous ROS such as OH; and 3) the high expression of reducing substances (e.g., glutathione, GSH) in the tumor microenvironment (TME) weakens the therapeutic effect of CDT. These limitations make it difficult for CDT alone to completely eliminate malignant tumors. Therefore, CDT-based combined treatment strategies have been widely developed. CDT-based combined therapy refers to the combination of CDT and other cancer treatments (e.g., photo-induced therapy, chemotherapy, sonodynamic therapy, starvation therapy, and gas therapy), which can produce a synergistic anticancer effect. This combined therapy can reduce individual drug-related toxicity and significantly enhance therapeutic efficiency, which has recently seen rapid development. This review begins by defining CDT, then it identifies the problems faced in CDT and proposes various strategies to enhance CDT performance, primarily focusing on CDT-based combined cancer treatment. The problems, opportunities, and challenges of CDT-based combination cancer therapy are also summarized, thereby providing a reference for the future development of CDT-based combined therapy.

Ultrafine Titanium Monoxide (TiO1+x) Nanorods for Enhanced Sonodynamic Therapy.

Ultrasound (US)-triggered sonodynamic therapy (SDT) that enables noninvasive treatment of large internal tumors has attracted widespread interest. For improvement in the therapeutic responses to SDT, more effective and stable sonosensitizers are still required. Herein, ultrafine titanium monoxide nanorods (TiO1+x NRs) with greatly improved sono-sensitization and Fenton-like catalytic activity were fabricated and used for enhanced SDT. TiO1+x NRs with an ultrafine rodlike structure were successfully prepared and then modified with polyethylene glycol (PEG). Compared to the conventional sonosensitizer, TiO2 nanoparticles, the PEG-TiO1+x NRs resulted in much more efficient US-induced generation of reactive oxygen species (ROS) because of the oxygen-deficient structure of TiO1+x NR, which predominantly serves as the charge trap to limit the recombination of US-triggered electron-hole pairs. Interestingly, PEG-TiO1+x NRs also exhibit horseradish-peroxidase-like nanozyme activity and can produce hydroxyl radicals (•OH) from endogenous H2O2 in the tumor to enable chemodynamic therapy (CDT). Because of their efficient passive retention in tumors post intravenous injection, PEG-TiO1+x NRs can be used as a sonosensitizer and CDT agent for highly effective tumor ablation under US treatment. In addition, no significant long-term toxicity of PEG-TiO1+x NRs was found for the treated mice. This work highlights a new type of titanium-based nanostructure with great performance for tumor SDT.

Fe-Doped Polyoxometalate as Acid-Aggregated Nanoplatform for NIR-II Photothermal-Enhanced Chemodynamic Therapy.

The combination of reactive oxygen species-involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe-doped polyoxometalate (Fe-POM) cluster is fabricated via a simple method. The Fe-POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near-infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less-reactive H2 O2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self-assembling properties at lowered pH values, the Fe-POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe-POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT-enhanced CDT in a NIR-II biowindow.

Bioinspired Construction of a Nanozyme-Based H2O2 Homeostasis Disruptor for Intensive Chemodynamic Therapy.

The insufficient intracellular H2O2 level in tumor cells is closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite tremendous efforts, engineering CDT agents with a straightforward and secure H2O2 supplying ability remains a great challenge. Inspired by the balance of H2O2 generation and elimination in cancer cells, herein, a nanozyme-based H2O2 homeostasis disruptor is fabricated to elevate the intracellular H2O2 level through facilitating H2O2 production and restraining H2O2 elimination for enhanced CDT. In the formulation, the disruptor with superoxide dismutase-mimicking activity can convert O2•- to H2O2, promoting the production of H2O2. Simultaneously, the suppression of catalase activity and depletion of glutathione by the disruptor weaken the transformation of H2O2 to H2O. Thus, the well-defined system could perturb the H2O2 balance and give rise to the accumulation of H2O2 in cancer cells. The raised H2O2 level would ultimately amplify the Fenton-like reaction-based CDT efficiency. Our work not only paves a way to engineer alternative CDT agents with a H2O2 supplying ability for intensive CDT but also provides new insights into the construction of bioinspired materials.

Reactive Oxygen Correlated Chemiluminescent Imaging of a Semiconducting Polymer Nanoplatform for Monitoring Chemodynamic Therapy.

In chemodynamic therapy (CDT), real-time monitoring of reactive oxygen species (ROS) production is critical to reducing the nonspecific damage during CDT and feasibly evaluating the therapeutic response. However, CDT agents that can emit ROS-related signals are rare. Herein, we synthesize a semiconducting polymer nanoplatform (SPN) that can not only produce highly toxic ROS to kill cancer cells but also emit ROS-correlated chemiluminescent signals. Notably, the efficacy of both chemiluminescence and CDT can be significantly enhanced by hemin doping (∼10-fold enhancement for luminescent intensity). Such ROS-dependent chemiluminescence of SPN allows ROS generation within a tumor to be optically monitored during the CDT process. Importantly, SPN establishes an excellent correlation of chemiluminescence intensities with cancer inhibition rates in vitro and in vivo. Thus, our nanoplatform represents the first intelligent strategy that enables chemiluminescence-imaging-monitored CDT, which holds potential in assessing therapeutic responsivity and predicting treatment outcomes in early stages.

Mo2 C-Derived Polyoxometalate for NIR-II Photoacoustic Imaging-Guided Chemodynamic/Photothermal Synergistic Therapy.

To overcome the current limitations of chemodynamic therapy (CDT), a Mo2 C-derived polyoxometalate (POM) is readily synthesized as a new CDT agent. It permits synergistic chemodynamic and photothermal therapy operating in the second near-infrared (NIR-II) biological transparent window for deep tissue penetration. POM aggregated in an acidic tumor micro-environment (TME) whereby enables specific tumor targeting. In addition to the strong ability to produce singlet oxygen (1 O2 ) presumably via Russell mechanism, its excellent photothermal conversion enhances the CDT effect, offers additional tumor ablation modality, and permits NIR-II photoacoustic imaging. Benefitting from the reversible redox property of molybdenum, the theranostics based on POM can escape from the antioxidant defense system. Moreover, combining the specific responsiveness to TME and localized laser irradiation, side-effects shall be largely avoided.

Mo2C‐Derived Polyoxometalate for NIR‐II Photoacoustic Imaging‐Guided Chemodynamic/Photothermal Synergistic Therapy

AbstractTo overcome the current limitations of chemodynamic therapy (CDT), a Mo2C‐derived polyoxometalate (POM) is readily synthesized as a new CDT agent. It permits synergistic chemodynamic and photothermal therapy operating in the second near‐infrared (NIR‐II) biological transparent window for deep tissue penetration. POM aggregated in an acidic tumor micro‐environment (TME) whereby enables specific tumor targeting. In addition to the strong ability to produce singlet oxygen (1O2) presumably via Russell mechanism, its excellent photothermal conversion enhances the CDT effect, offers additional tumor ablation modality, and permits NIR‐II photoacoustic imaging. Benefitting from the reversible redox property of molybdenum, the theranostics based on POM can escape from the antioxidant defense system. Moreover, combining the specific responsiveness to TME and localized laser irradiation, side‐effects shall be largely avoided.

Copper(I) Phosphide Nanocrystals for In Situ Self‐Generation Magnetic Resonance Imaging‐Guided Photothermal‐Enhanced Chemodynamic Synergetic Therapy Resisting Deep‐Seated Tumor

AbstractFe‐based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the strict condition (lower pH environment: 3–4) of the highly efficient Fenton reaction limits its practical application in the clinic. Development of new CDT agents more suitable for TME is significant and challenging. A highly efficient Cu(I)‐based CDT agent, copper(I) phosphide nanocrystals (CP NCs), which is more adaptable to the pH value of TME than Fe‐based agents, thereby producing more ·OH to trigger the apoptosis of cancer cells, is prepared. Moreover, the excess glutathione (GSH) in TME can reduce the Cu(II) produced by a Fenton‐like reaction to Cu(I), further increasing the generation rate of ·OH and relieving tumor antioxidant ability. Furthermore, owing to their strong absorption in the NIR II region, CP NCs exhibit an excellent photothermal conversion effect, which can further improve the Fenton reaction. What is more, CP NCs can act as in situ self‐generation magnetic resonance imaging (MRI) agents owing to the generation of paramagnetic Cu(II) in response to excess H2O2 in the TME. These properties may open up the exploration of copper‐based materials in clinical application of self‐generation imaging‐guided synergetic treatment.

Synthesis of Copper Peroxide Nanodots for H2O2 Self-Supplying Chemodynamic Therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2 -Based Nanoagent to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) utilizes iron-initiated Fenton chemistry to destroy tumor cells by converting endogenous H2 O2 into the highly toxic hydroxyl radical (. OH). There is a paucity of Fenton-like metal-based CDT agents. Intracellular glutathione (GSH) with . OH scavenging ability greatly reduces CDT efficacy. A self-reinforcing CDT nanoagent based on MnO2 is reported that has both Fenton-like Mn2+ delivery and GSH depletion properties. In the presence of HCO3- , which is abundant in the physiological medium, Mn2+ exerts Fenton-like activity to generate . OH from H2 O2 . Upon uptake of MnO2 -coated mesoporous silica nanoparticles (MS@MnO2 NPs) by cancer cells, the MnO2 shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn2+ , resulting in GSH depletion-enhanced CDT. This, together with the GSH-activated MRI contrast effect and dissociation of MnO2 , allows MS@MnO2 NPs to achieve MRI-monitored chemo-chemodynamic combination therapy.