Chemodynamic Therapy Research Articles

Transition Metal (Molybdenum)-Doped Drug-like Conformational Nanoarchitectonics with Altered Valence States (Mn2+/Mn4+ and Mo5+/Mo6+) for Augmented Cancer Theranostics.

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 (MnO2) nanoarchitectures, exhibiting diagnostic (magnetic resonance imaging, MRI) and therapeutic (chemodynamic therapy, CDT) functionalities. The facile hydrothermal approach-assisted Mo-doped MnO2 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 (Mn2+/Mn4+ and Mo5+/Mo6+) 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 MnO2 nanoparticles displayed excellent MRI efficacy in vitro. Together, we believe that these conformational Mo-doped MnO2 nanoarchitectures with two pairs of variable valence states could potentiate drugless therapy in pharmaceutics.

Intelligent Hydrogel with Physiologically Dependent Capacities of Photothermal Conversion and Nanocatalytic Medicine to Integratively Inhibit Bacteria and Inflammation for On-Demand Treatment of Infected Wound.

Although chemodynamic therapy (CDT) and photothermal therapy (PTT) based on a variety of nanoparticles have been developed to achieve effective anti-bacterial therapy, the limited therapeutic efficiency of CDT alone, as well as the undifferentiated damage of PTT to both bacteria and surrounding healthy tissue are still challenges for their clinical application of infected wounds treatments. In addition, during the CDT and PTT-mediated antimicrobial processes, the endogenous macrophages would be easily converted to pro-inflammatory macrophages (M1 phenotype) under local ROS and hyperthermia to promote inflammation, resulting in unexpected suppression of tissue regeneration and possible wound deterioration. To address these problems, a biodegradable sodium alginate/hyaluronic acid hydrogel loaded with functional CeO2-Au nano-alloy (AO@ACP) is fabricated to not only achieve precise and efficient antibacterial activity through infection-environment dependent photothermal-chemodynamic therapy but also rapidly eliminate the excess reactive oxygens (ROS) in the M1 type macrophage at the infected area to induce their polarization to M2 type for significant inhibition of inflammation and remarkable enhancement of tissue regeneration, hopefully developing an effective strategy to treat infected wound.

NIR-Actuated Ferroptosis Nanomotor for Enhanced Tumor Penetration and Therapy.

Ferroptosis nano-inducers have drawn considerable attention in the treatment of malignant tumors. However, low intratumoral hydrogen peroxide level and complex biological barriers hinder the ability of nanomedicines to generate sufficient reactive oxygen species (ROS) and achieve tumor penetration. Here a near-infrared (NIR)-driven ROS self-supplying nanomotor is successfully designed for synergistic tumor chemodynamic therapy (CDT) and photothermal therapy (PTT). Janus nanomotor is created by the asymmetrical modification of polydopamine (PDA) with zinc peroxide (ZnO2) and subsequent ferrous ion (Fe2+) chelation via the polyphenol groups from the PDA, here refer as ZnO2@PDA-Fe (Z@P-F). ZnO2 is capable of slowly releasing hydrogen peroxide (H2O2) into an acidic tumor microenvironment (TME) providing sufficient ingredients for the Fenton reaction necessary for ferroptosis. Upon NIR laser irradiation, the loaded Fe2+ is released and a thermal gradient is simultaneously formed owing to the asymmetric PDA coating, thus endowing the nanomotor with self-thermophoresis based enhanced diffusion for subsequent lysosomal escape and tumor penetration. Therefore, the release of ferrous ions (Fe2+), self-supplied H2O2, and self-thermophoresis of nanomotors with NIR actuation further improve the synergistic CDT/PTT efficacy, showing great potential for active tumor therapy.

A red cell membrane-camouflaged nanoreactor for enhanced starvation/chemodynamic/ion interference therapy for breast cancer

In this study, a multifunctional Cu-doped CaO2 nanoreactor loaded with GOx and camouflaged with a folic acid-modified cell membranewas developed for breast cancer treatment. The as-developed composite nanoreactor showed a synergistic effect on calcium overload to damage mitochondria, thus killing tumor cells to achieve ion interference therapy (IIT). The loaded GOx could deplete glucose to “starve” tumor cells. The H2O2 released by CaO2 decomposition and enzyme catalytic reactions from GOx could not only be highly toxic in the tumor microenvironment but also enhance the efficiency of chemodynamic therapy (CDT) with Cu2+. The red blood cell membranes modified by folic acid achieved a combination of active targeting and passive targeting, thereby enhancing the targeting ability of the as-prepared multifunctional composite nanoreactor and prolonging its retention time at the tumor sites for more than 48 h.

In vivo self-assembled albumin nanoparticle elicit antitumor immunity of PD-1 inhibitor by imaging and clearing tumor-associated macrophages.

Eliciting anti-tumor immune responses and improving the tumor microenvironment crucial for boosting the effectiveness of anti-PD-1 immunotherapy. Tumor-associated macrophages (TAMs), the primary types of immune cells infiltrating tumors, play a critical role in the formation of an immunosuppressive microenvironment. In this study, we constructed a novel Evans Blue (EB)-based in vivo self-assembled nanocarrier system, mUNO-EB-ICG-Fc@Alb nanoparticles (designated as MA NPs), for targeted imaging and clearance of M2-TAMs to elicit antitumor immunotherapy of PD-1 inhibitor. In vitro experiments demonstrated the specific fluorescence imaging and killing effect of MA NPs on M2-TAMs. In vivo experiments shown that MA NPs-induced chemodynamic therapy (CDT) successfully reversed the tumor immunosuppressive microenvironment (ITM), promoted intratumoral infiltration of T lymphocytes, and ultimately enhancing the anti-tumor immunotherapy effect of PD-1 inhibitors. This study might provide good inspiration for improving the therapeutic efficacy of cancer immunotherapy.

Photothermally reinforced chemodynamic therapy in the treatment of osteosarcoma by polydopamine-modified, copper peroxide loaded ZIF8 nanoparticles

Chemodynamic therapy (CDT) has played an important role in osteosarcoma (OS) treatment. However, the insufficient content of endogenous H2O2 and high expression of glutathione (GSH) in tumor tissues limit the antitumor efficacy of CDT. In this work, we developed polydopamine (PDA) coated and CuO2 NPs loaded ZIF8 nanoparticles (CuO2@ZIF8@PDA NPs) for thermally reinforced CDT treatment of OS. The CuO2@ZIF8@PDA NPs exhibited excellent stability in neutral solutions while degraded in weakly acidic environments to generate hydrogen peroxide (H2O2) and Cu2+. Cu2+ consumes GSH in tumor tissues to generate Cu+. Both Cu2+ and Cu+ catalyzed the decomposition of H2O2, triggering a Fenton-like reaction to produce hydroxyl radicals (•OH). The PDA coating endowed the nanosystem with photothermal conversion capabilities under near-infrared laser irradiation, further promoting the generation of •OH, and inducing tumor cell death. In vitro experiments demonstrated that CuO2@ZIF8@PDA NPs exhibited significant toxicity towards K7M2 cells while remaining non-toxic to normal cells. In vivo studies revealed that under 808 nm laser irradiation, CuO2@ZIF8@PDA NPs exhibited stronger killing ability against K7M2 cells than CuO2@ZIF8@PDA NPs alone. This system, which combines GSH depletion, intratumoral H2O2 self-generation, and photothermally enhanced CDT, holds great promise for playing a pivotal role in the treatment of osteosarcoma.

A multifunctional nanosystem catalyzed by cascading natural glucose oxidase and Fe3O4 nanozymes for synergistic chemodynamic and photodynamic cancer therapy

The significance of the tumor microenvironment (TME) in tumor initiation and progression is increasingly acknowledged. Conventional therapeutic approaches face limitations within the complex TME, including the restrictions imposed by hypoxia on photodynamic therapy (PDT) and the deficiency of endogenous H₂O₂ affecting chemodynamic therapy (CDT). In response to the TME's characteristics of high metabolism, hypoxia, and weak acidity, a multifunctional nanosystem MNPs/GOD@CS/IR820, which synergistically integrates CDT and PDT, has been developed. This system can actively accumulate at tumor sites under an external magnetic field and release active components in response to the weakly acidic TME. It mitigates the limitations imposed by hypoxia and endogenous H₂O₂ deficiency on PDT and CDT, respectively, thereby enabling synergistic treatment. Additionally, the system's multimodal imaging capabilities facilitate precise tumor localization and real-time, non-invasive in vivo assessment via fluorescence imaging and MRI. In vitro and in vivo evaluations demonstrate significant antitumor efficacy, effectively inhibiting tumor growth and improving survival rates. By comprehensively addressing the challenges posed by the complex TME and enhancing real-time monitoring capabilities, our nanosystem paves the way for personalized and precise cancer treatment. Statement of significanceThis study introduces an innovative MNPs/GOD@CS/IR820 nanosystem that represents a significant advancement in cancer nanomedicine by addressing critical limitations of conventional photodynamic therapy (PDT), particularly in hypoxic tumor microenvironments. By synergistically integrating chemodynamic therapy (CDT) with PDT and incorporating MRI and fluorescence dual-modal imaging capabilities, this multifunctional platform offers enhanced therapeutic efficacy and real-time monitoring. The system's ability to generate oxygen in situ overcomes hypoxia-induced limitations, while its multimodal mechanism of action induces tumor cell apoptosis through multiple pathways. In vitro and in vivo studies demonstrate remarkable antitumor efficacy across diverse cancer types, significantly inhibiting tumor growth and improving survival rates. This comprehensive approach to cancer diagnosis and treatment not only advances precision medicine for targeted, multimodal cancer management but also provides a promising foundation for future clinical applications, potentially transforming cancer treatment strategies and improving patient outcomes.

Injectable hydrogels for Fenton-like Mn2+/Fe2+ delivery with enhanced chemodynamic therapy prevent osteosarcoma recurrence and promote wound healing after excision surgery

Local recurrence of osteosarcoma and wound healing after excision surgery are major challenges in clinical research. The present anti-tumor treatments could inhibit normal tissues, resulting in difficulties in surgical wound healing. In this study, we constructed an injectable hydrogel as a platform to co-deliver MnO2 nanoparticles and ferrocene Fc, termed as (MnO2/Fc)@PLGA for osteosarcoma treatment and wound healing after excision. By simple local injection, the hydrogel could form a protective barrier on the surgical wound after osteosarcoma excision, which could promote wound healing and steady release of MnO2/Fc nanoparticles. The released MnO2/Fc might undergo the Fenton reaction through Mn2+/Fe2+ to inhibit osteosarcoma cells with chemodynamic therapy (CDT). Furthermore, MnO2 could catalyze endogenous H2O2 to produce O2, which eliminates the adverse effects of H2O2 and remodels the hypoxic state in the local lesions. The increased O2 facilitated surgical wound healing and anti-tumor effects by regulating the hypoxia inducible factor-1 functions. In conclusion, (MnO2/Fc)@PLGA hydrogel could effectively prevent local recurrence of osteosarcoma and promote wound healing after excision surgery, thereby providing a novel strategy for tumor treatment and tissue repair.

Injectable hydrogel assisted formation of hydroxyl radical generating bioreactor enables photothermally enhanced chemodynamic and immunotherapy

Photothermal therapy and chemodynamic therapy (CDT), two recently invented cancer treatments, have shown to be effective in potentiating immunotherapy through causing immunogenic cancer cell death. The rational integration of these two therapeutic modalities poses a formidable challenge in eliciting robust immunotherapy. Herein, an injectable hydrogel based bioreactor comprising of glucose oxidase (GOx), copper sulfide (CuS) nanoparticles, and poly (ethylene glycol) double acrylate (PEGDA) is prepared to potentiate immune checkpoint blockade (ICB) therapy. GOx can in situ convert glucose to hydrogen peroxide (H2O2) and gluconic acid, the latter of which further promotes the decomposition of H2O2 to hydroxyl radicals by creating an acidic microenvironment to benefit the pH-dependent Fenton-like catalytic reaction of Cu+, particularly in synergizing with near infrared (NIR) light exposure. Such catalytic couple of GOx and CuS together with NIR light exposure is efficient in inducing immunogenic cancer cell death. Additionally, GOx reprogrammed tumor immunosuppressive microenvironment by reducing lactate levels. Upon being fixed inside tumors with PEGDA hydrogel, such in situ formed bioreactor effectively suppresses the growth of 4T1 orthotopic murine breast cancers in Balb/c mice together with 808 nm laser exposure. Furthermore, such bioreactor enabled photothermally enhanced CDT could also synergize with anti-PD-L1 immunotherapy to more effectively suppress the growth of primary tumors and distant tumors. This study highlights that such NIR light and reactive oxygen species dual responsive bioreactor is robust to potentiate ICB immunotherapy.

Dual-activity nanozyme as an oxygen pump to alleviate tumor hypoxia and enhance photodynamic/ NIR-II photothermal therapy for sniping oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region, and its treatment is limited by hypoxia and inadequate oxygen supply. Continuous oxygen delivery combined with photodynamic therapy (PDT) is the key to addressing this issue. Here, a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform was designed to serve as an "oxygen pump" to alleviate tumor hypoxia for synergistic photodynamic/photothermal therapy (PTT). In this design, the photosensitizer chlorin e6 (Ce6) is covalently linked to the Au@Pt nanozyme for PDT treatment. The Au@Pt nanozyme exhibits catalase-like activity, continuously decomposing H2O2 in the tumor microenvironment to enhance O2 levels, thereby achieving efficient PDT. Furthermore, Au@Pt can perform PTT and increase oxygen levels under NIR-II light to further promote PDT. The Au@Pt nanozyme also exhibits peroxidase-like activity, generating ·OH for chemodynamic therapy (CDT). Additionally, HN-1 guides the direction of "sniping" OSCC, and its high specificity benefits Au@Pt-Ce6-HN-1 at the tumor site. Au@Pt-Ce6-HN-1 exhibits bright fluorescence (FL), strong CT signal, and photothermal imaging capabilities, laying the foundation for subsequent guided PDT/PTT. This nanoplatform, which combines advantages such as continuous oxygen production, tumor targeting, and multimodal imaging, is expected to provide valuable insights into the treatment of OSCC. Statement of significanceAccurate clinical diagnosis and treatment of OSCC are challenging. We report a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform, serving as an "oxygen pump" to guide photodynamic therapy (PDT) and photothermal therapy (PTT) for OSCC. This nanoplatform targets OSCC for preoperative CT diagnosis and offers fluorescence visualization for surgical navigation, demonstrating potential in clinical cancer detection and surgery guidance. This innovative approach addresses OSCC hypoxia and enhances treatment efficacy through continuous oxygen production, tumor targeting, and multimodal imaging, significantly improving patient outcomes in OSCC treatment.

3D DNAzyme Motor Nanodevice With Self-Powered FRET Amplifier and Self-Supplied H2O2 for Enhancing Human Neutrophil Elastase Profiling and Chemodynamic Therapy in Lung Tumor.

The development of theragnostic nanosystems integrating FRET (fluorescence resonance energy transfer) imaging and chemodynamic therapy (CDT) for accurate diagnosis and effective treatment of lung tumors is still a big challenge. Herein, a peptide-assembled 3D DNAzyme motor nanodevice is engineered for a self-powered FRET amplifier profiling human neutrophil elastase (HNE) and self-supplied H2O2 enhancing CDT. The nanodevice is prepared by depositing AuNPs on ZIF-8, in which ZIF-8 co-loaded the lysosomal targeting peptide-modified copper peroxides (PCPs) and hairpins (H1, H2, and H3), AuNPs are co-labeled by DNAzyme-peptide (DP) conjugate and H3. In the tumor micro-environment, HNE driven 3D DNAzyme walker followed by an exponential amplification constructed by a synergistic cross-activation between hybridization chain reaction and DNAzyme, generating a self-powered FRET amplifier. The FRET amplifier specifically measures HNE with a sensitivity of 0.026pM, and successfully images exogenous HNE in living cells and monitors HNE in mouse models. Moreover, the PCPs can target lysosomes, reducing lysosome escape. The self-supplying H2O2 undertaken by PCPs improves the Cu (II)-catalyzed Fenton-like reaction, effectively causing cell apoptosis to inhibit tumor growth. Significantly, the nanodevice successfully screens inhibitors and discriminates the HNE level in normal and lung cancer tissues, suggesting that the nanodevice provides an effective tool for the diagnosis and treatment of lung tumors.

Zn/Cu Bi‐Single‐Atom Nanoplatform: Hexagonal Anti‐Tumor Warrior by ROS Amplification for DOX Resistance Reversal and Immune Activation

AbstractSevere resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H2O2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes.

GSH responsive AuNRs@TFF nanotheranostic for NIR-II photoacoustic imaging-guided CDT/PTT synergistic cancer therapy

Gold nanorods (AuNRs) are important photothermal therapeutic agents; however, a single therapy does not achieve satisfactory outcomes, and the synthesis process often leads to the adsorption of cetyltrimethylammonium bromide on the surface of AuNRs, which reduces its biocompatibility. Natural polyphenols are abundant in natural plants and have good biocompatibility. The metal-polyphenol network is formed by the coordination of metal ions and polyphenols, which has good drug loading, surface adhesion, and biocompatibility. In this study, the metal-polyphenol network structure formed by a transition metal (iron) and natural polyphenol tannic acid was used to modify the surface of gold nanorods (AuNRs@TF). Additionally, the surfaces of AuNRs were modified using the targeted functional molecule mercapto folic acid (AuNRs@TFF). The constructed composite nanomaterials AuNRs@TFF has good biocompatibility and tumor targeting ability. Tannic acid‑iron degrades in the tumor microenvironment and releases iron ions that catalyze the Fenton reaction, thereby facilitating chemodynamic therapy. The good photo-thermal ability of AuNRs generate good photoacoustic signals to facilitate photoacoustic imaging mediation and enhances photothermal and chemodynamic therapy performance. This study expands on the application of AuNRs in the field of nanomedicine. The simple and effective design of AuNRs@TFF provides a strategy for the development of synergistic therapeutic agents for photothermal therapy and chemodynamic therapy.

Adenosine triphosphate-responsive carbon dots nanoreactors for T1-weighted magnetic resonance imaging-guided tumor chemodynamic therapy

Adenosine triphosphate-responsive carbon dots nanoreactors for T1-weighted magnetic resonance imaging-guided tumor chemodynamic therapy

Tumor Microenvironment-Responsive Biodegradable Nanomedicine for Self-Enhanced Synergistic Chemo-, Photothermal, and Chemodynamic Therapy.

The nanoscale multidrug codelivery system for synergistic therapy is an effective strategy for tumor treatment. However, the low drug delivery efficiency and poor therapeutic effects limit its application. Here, based on the coordination effect of Artemisinin (Art), quercetin (Qc), and Fe3+, we had constructed a safe and efficient carrier-free hyaluronic acid (HA)-modified Art-Fe-Qc nanoparticles (AFQ@HA NPs) for enhanced chemotherapy/photothermal therapy (PTT)-chemodynamic therapy (CDT) synergistic therapy, which achieved an ultrahigh drug loading efficiency and a multifunction anticancer strategy. The results showed that high drug loading was achieved based on drug coordination self-assembly, with Art and Qc contents of 38.6 and 42.7%, respectively. At the same time, based on the Qc-Fe coordination molecular network, the system had excellent photothermal conversion performance with an efficiency of 57.3% and could effectively inhibit the expression of HSP70, achieving enhanced PTT. Further, under the stimulation of excessive H2O2 and glutathione (GSH) in the tumor microenvironment, the AFQ@HA NPs were continuously degraded, while releasing Art and Fe3+/Fe2+ to achieve iron ion-enhanced CDT. The results of in vitro and in vivo experiments showed that AFQ@HA NPs could achieve chemotherapy-PTT-CDT synergistic therapy in response to tumor microenvironment by passively targeting and actively targeting tumor cells with CD44, demonstrating its excellent targeted antitumor effects.

Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review

Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review

Cu2O-SnO2-PDA heterozygous nanozyme doped hydrogel mediated conglutinant microenvironment regulation for wound healing therapy

Bacterial infection significantly hinders the wound healing process. Overuse of antibiotics has led to the rise of drug resistance in bacteria, making the development of smart medical dressings that promote wound healing without antibiotics, a critical need. In this study, Cu₂O-SnO₂-PDA (PCS) nanoenzymes with Fenton-like activity and high photothermal conversion efficiency were developed. These nanoenzymes were then incorporated into a hydrogel through cross-linking of acrylamide (AM) and N-[Tris-(hydroxymethyl)methyl] acrylamide (THMA), forming a tough, highly-adhesive, and self-healing composite hydrogel (AT/PCS) with antimicrobial properties. The AT/PCS hydrogel exhibits excellent mechanical strength and adhesion, facilitating increased oxygen levels and strong adherence to the wound site. Moreover, it effectively regulates the wound microenvironment by combining synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT) for antibacterial treatment. The AT/PCS hydrogel enhances collagen deposition and expedites wound healing in a rat model, largely due to its potent antibacterial properties.

A BODIPY-Ferrocene Conjugate for the Combined Photodynamic Therapy and Chemodynamic Therapy with Improved Antitumor Efficiency.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and ⋅OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.

Tumor Microenvironment-Activated In Situ Synthesis of Peroxynitrite for Enhanced Chemodynamic Therapy.

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 H2O2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H2O2 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.

NIR‐Triggered Cu2O/Cu2‐xS Heterostructure as an “All‐In‐One” Functional Nanoplatform for Efficient Synergistic Tumor Therapy

AbstractThe fabrication of synergistic multifunctional anti‐tumor nanoplatforms is challenging due to the urgent requirement to activate different therapeutic modalities. Although the multi‐modal treatments can be achieved by carrying out the activation with different exogenous and endogenous stimulations in sequence, this tedious manner is not applicable to the ideal synergistic cancer treatment. Herein, a simple heterojunction of Cu2O/Cu2‐xS modified with gambogic acid and hyaluronic acid (CCS@GA@HA) is ingeniously fabricated for the synergistic cancer treatment combining photothermal therapy (PTT), photocatalytic therapy (PCT), chemodynamic therapy (CDT) and potential ferroptosis just activated by the single near infrared (NIR) light irradiation. Cu2O/Cu2‐xS heterostructure (CCS) with promoted separation and transfer efficiency of photogenerated charge carriers exhibits excellent photocatalytic performance. The intervention of gambogic acid (GA) downregulates the overexpression of heat shock protein 90 (HSP90), which make it possible to execute the mild PTT. And the CDT performance is efficiently improved by the heat generated from PTT. Specifically, CCS appears to accelerate the accumulation of lipid peroxides (LPO) and inactivate glutathione peroxidase 4 (GPX4) that directly induce ferroptosis. In brief, CCS@GA@HA exhibits prominent NIR‐triggered synergistic effect involving PCT, mild PTT, enhanced CDT and ferroptosis for an effective multi‐modal tumor treatment.