Synergistic Starvation Research Articles

One stone, three birds: Construction of Cu/ZIF-8@DSF@GOx/HA nanoplatform for synergistic starvation therapy enhanced chemo−/chemodynamic therapy

Disulfiram (DSF), as a sixpenny drug for the treatment of alcohol dependence, has demonstrated copper-dependent chemotherapy (CT) effects in recent years. However, as the most common modality in clinical treatment, prolonged use of CT will lead to multidrug resistance (MDR). In this work, a versatile and ingenious nanoparticle Cu/ZIF-8@DSF@GOx/HA (CZDGH) was constructed to deliver DSF, Cu2+ and GOx to tumor cells. Once internalized by tumor cells, GOx depletes glucose blocking the energy supply leading to ST. Then DSF chelates with Cu2+ in situ to generate CuETs, achieving toxicity-intensified CT, the reduced ATP in this process also inhibits the efflux function of P-gp. In the meantime, Cu2+ consumes glutathione (GSH) to enhance oxidative stress, and the converted Cu+ catalyzes internal and external sources of H2O2 into •OH, heightening chemodynamic therapy (CDT). The experimental results demonstrate remarkable multimodal synergistic anticancer effects that overcome MDR.

Hollow Mesoporous MnO2 Nanospheres as Light Source-Free Carriers for Synergistic Starvation and Chemiexcited Photodynamic Tumor Therapy

Hollow Mesoporous MnO₂ Nanospheres as Light Source-Free Carriers for Synergistic Starvation and Chemiexcited Photodynamic Tumor Therapy

Cascaded Nanozyme with In Situ Enhanced Photothermal Capacity for Tumor-Specific and Self-Replenishing Cancer Therapy.

Reactive oxygen species (ROS)-involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H2 O2 level in the tumor microenvironment. Here, peroxidase (POD)-like RuTe2 nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3',5,5'-tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe2 -GOx-TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor-specific and self-replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H2 O2 for subsequent Fenton-like reactions catalyzed by RuTe2 nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor-specific "turn-on" photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti-tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency.

“Domino” cascade reactor based on DNA hydrogel for synergistic treatment of malignant tumor

The action pathways of starvation therapy and photodynamic therapy (PDT) do not exist in isolation and are usually related to tumor cell metabolism and immune regulation, which are of great significance in the treatment of malignant tumors. Here, a cancer-targeted “domino” cascade reactor is constructed for synergistic starvation therapy and amplifies photodynamic therapy by assembling hemin and glucose oxidase (GOx) into DNA hydrogel load with hypoxia-inducible factor 1α (HIF-1α) and photosensitizer chlorin e6 (Ce6). The cascade reactor has excellent biocompatibility and tumor targeting, which promotes PDT by reducing HIF-1α. At the same time, the G-quadruplex of AS1411 combined with hemin (AH) catalyzes the generation of oxygen from hydrogen peroxide to further improve the efficiency of PDT. The synergistic therapeutic effect of the cascade reactor is evaluated through in vivo and in vitro experiments, indicating that this cascade reactor has great potential advantages in the synergistic treatment of cancer.

Dual-Functional Nanoplatform Based on Bimetallic Metal-Organic Frameworks for Synergistic Starvation and Chemodynamic Therapy.

Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied in oral squamous cell carcinoma. However, the low catalytic efficiency due to insufficient H2O2 in the TME is still a major challenge for its clinical translation. Herein, we present an antitumor nanoplatform based on a Mn-Co organometallic framework material (MnCoMOF), which shows peroxidase-like (POD-like) activity, loaded with glucose oxidase (GOx@MnCoMOF), demonstrating the ability of H2O2 self-supply and H2O2 conversion to toxic hydroxyl radicals. The encapsulated GOx efficiently catalyzes glucose into gluconic acid and H2O2 at the tumor site, which can cut off the energy supply to inhibit tumor growth and produce a large amount of H2O2 and acid to compensate for their lack in the tumor microenvironment. The POD-like activity of MnCoMOF can convert H2O2 into hydroxyl radicals and eliminate tumor cells. The nanoplatform exhibits enhanced tumor cell cytotoxicity in a high-glucose medium compared with a low-glucose medium, illustrating sufficient generation of H2O2 from glucose by GOx. The in vivo results indicate that GOx@MnCoMOF has excellent antitumor efficacy and can remodel the immune-suppressive tumor microenvironment. In conclusion, the GOx@MnCoMOF nanoplatform possesses dual enzymatic activities, i.e., POD-like and glucose oxidase, to achieve improved tumor-suppressive efficiency through synergistic starvation and chemodynamic therapy, thus providing a new strategy for the clinical treatment of oral cancer.

A pH-Responsive Charge-Convertible Drug Delivery Nanocarrier for Precise Starvation and Chemo Synergistic Oncotherapy.

A pH-responsive charge-convertible drug delivery nanocarrier (MSN-TPZ-GOx@ZnO@PAH-PEG-DMMA, abbreviated as MTGZ@PPD) was prepared, which could specifically release hypoxia-activated chemotherapeutic Tirapazamine (TPZ) and glucose oxidase (GOx) in the tumor site for precise starvation and chemo synergistic oncotherapy. Acid-responsive Schiff base structure modified mesoporous silica nanoparticles (MSN) co-load with GOx and TPZ, then link with ZnO quantum dots (QDs). PAH-PEG-DMMA (PPD) polymer makes MTGZ@PPD with biocompatibility and charge-convertible feature. MTGZ@PPD is negatively charged at physiological pH, and the charge reversal of PPD and acidolysis of the Schiff base structure under the acidic tumor microenvironment (TME) induce a positively charged surface, which could potentiate the cell internalization. ZnO QDs could decompose at acidic TME, achieving controllable drug release. GOx could starve the tumor cells and enhance hypoxia level, thus initiates the activation of TPZ to realize synergistic starvation therapy and chemotherapy. This intelligent MTGZ@PPD has shown great potential for starvation and chemo synergistic oncotherapy.

NIR-IIb fluorescence-image guided synergistic surgery/starvation/chemodynamic therapy: an innovative treatment paradigm for malignant non-small cell lung cancers.

Background: Currently, the prognosis and survival rate for patients bearing non-small cell lung cancer (NSCLC) is still quite poor, mainly due to lack of efficient theranostic paradigms to exert in time diagnostics and therapeutics. Methods: Herein, for NSCLC treatment, we offer a customized theranostic paradigm, termed NIR-IIb fluorescence diagnosis and synergistic surgery/starvation/chemodynamic therapeutics, with a newly designed theranostic nanoplatform PEG/MnCuDCNPs@GOx. The nanoplatform is composed of brightly NIR-II emissive downconversion nanoparticles (DCNPs)-core and Mn/Cu-silica shell loaded with glucose oxidase (GOx) to achieve synergistic starvation and chemodynamic therapy (CDT). Results: It is found that 10% Ce3+ doped in the core and 100% Yb3+ doped in the middle shell greatly improves the NIR-IIb emission up to even 20.3 times as compared to the core-shell DCNPs without Ce3+ doping and middle shell. The bright NIR-IIb emission of the nanoplatform contributes to sensitive margin delineation of early-stage NSCLC (diameter < 1 mm) with a signal-to-background ratio (SBR) of 2.18, and further assists in visualizing drug distribution and guiding surgery/starvation/chemodynamic therapy. Notably, the starvation therapy mediated by GOx-driven oxidation reaction efficiently depletes intratumoral glucose, and supplies H2O2 to boost the CDT mediated by the Mn2+ and Cu2+, which consequently realized a highly effective synergistic treatment for NSCLC. Conclusion: This research demonstrates an efficient treatment paradigm for NSCLC with NIR-IIb fluorescence diganosis and image-guided synergistic surgery/starvation/chemodynamic therapeutics.

A Cascade Nanoreactor of Metal-Protein-Polyphenol Capsule for Oxygen-Mediated Synergistic Tumor Starvation and Chemodynamic Therapy.

Starvation therapy kills tumor cells via consuming glucose to cut off their energy supply. However, since glucose oxidase (GOx)-mediated glycolysis is oxygen-dependent, the cascade reaction based on GOx faces the challenge of a hypoxic tumor microenvironment. By decomposition of glycolysis production of H2 O2 into O2 , starvation therapy can be enhanced, but chemodynamic therapy is limited. Here, a close-loop strategy for on demand H2 O2 and O2 delivery, release, and recycling is proposed. The nanoreactor (metal-protein-polyphenol capsule) is designed by incorporating two native proteins, GOx and hemoglobin (Hb), in polyphenol networks with zeolitic imidazolate framework as sacrificial templates. Glycolysis occurs in the presence of GOx with O2 consumption and the produced H2 O2 reacts with Hb to produce highly cytotoxic hydroxyl radicals (•OH) and methemoglobin (MHb) (Fenton reaction). Benefiting from the different oxygen carrying capacities of Hb and MHb, oxygen on Hb is rapidly released to supplement its consumption during glycolysis. Glycolysis and Fenton reactions are mutually reinforced by oxygen supply, consuming more glucose and producing more hydroxyl radicals and ultimately enhancing both starvation therapy and chemodynamic therapy. This cascade nanoreactor exhibits high efficiency for tumor suppression and provides an effective strategy for oxygen-mediated synergistic starvation therapy and chemodynamic therapy.

Cascade-Enhanced Catalytic Nanocomposite with Glutathione Depletion and Respiration Inhibition for Effective Starving-Chemodynamic Therapy Against Hypoxic Tumor.

Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT. In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment. The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.

Drug-Induced Self-Assembly Cascade Nanoreactor for Synergistic Tumor Therapy.

The construction of completely biocompatible and biodegradable tumor suppressors by a simple and reliable method is essential for the clinical application of cancer-targeted drugs. Herein, by inserting glucose oxidase (GOx), catalase (CAT), and chlorin e6 (Ce6) into human serum albumin (HSA) assembly molecules, we constructed a cancer-targeted cascade bioreactor for synergistic starvation and photodynamic therapy (PDT). The modification of HSA could block the GOx activity and reduce the cytotoxicity of normal cells and organs. Through active targeting and passive enhanced permeability and retention effect, the loading of AS1411 could promote the cascade bioreactors to effectively target nucleolin-overexpressed tumors. Once internalized by cancer cells, as a result of catalyzing hydrogen peroxide (H2O2) to produce oxygen (O2), the protein nano-cascade reactor promoted microenvironmental oxygenation, which would subsequently lead to an increase in cytotoxic singlet oxygen (1O2) production under light irradiation as well as the decomposition of intracellular glucose. In vitro and in vivo studies showed that the cascaded nanoreactors could significantly enhance therapeutic efficacy through synergistic starvation therapy and enhanced PDT as well as chemotherapy. This cascade strategy will be demonstrated in clinical applications with huge potential.

A Noble AuPtAg-GOx Nanozyme for Synergistic Tumor Immunotherapy Induced by Starvation Therapy-Augmented Mild Photothermal Therapy.

Notwithstanding immune checkpoint blocking (ICB) therapy has made eminent clinical breakthroughs, overcoming immunologically "cold" tumors remains challenging. Here, a cascade potentiated nanomodulator AuPtAg-GOx is engineered for boosting immune responsiveness. Upon 1064nm laser irradiation, AuPtAg-mediated mild photothermal therapy (PTT) activates cytotoxic T lymphocytes and reverses the immunogenic "cold" tumor microenvironment. Further, to amplify the thermal sensitivity of tumor cells, glucose oxidase (GOx) is introduced to suppress the production of heat shock proteins, thereby promoting mild photothermal therapy. Complementarily, AuPtAg nanozymes with catalase-like activity can ameliorate tumor hypoxia, significantly improving the GOx activity. As a result, the combination of AuPtAg-GOx with self-augmented photothermal ability and PD-L1 antibody can further escalate the antitumor efficacy. The AuPtAg-GOx-based synergistic starvation therapy, mild PTT, and immunotherapy cascade enhancement therapy strategy can be a favorable tool to effectively kill cancer cells.

A self-supplied O2 versatile nanoplatform for GOx-mediated synergistic starvation and hypothermal photothermal therapy

Hypothermal photothermal therapy, as a non-invasive therapy method, is becoming ever more prevalent. However, due to cellular heat resistance from the generation of heat shock proteins (HSPs) and the monotonicity of therapeutic modality, the antitumor efficacy is severely restricted. Herein, a self-supplied O2 multifunctional nanoplatform mediated by glucose oxidase (GOx) is developed, which may combine starvation therapy (ST) and hypothermal photothermal therapy (HPTT) for tumor therapy. The obtained nanoplatform, UM@ICG@GOX@HA (UMIGH), was assembled by the UIO-66 core, MnO2, indocyanine green (ICG) and hyaluronic acid (HA). GOx was introduced to decrease the ATP level thus alleviating the HSPs-mediated heat tolerance, while the loaded MnO2 could decompose intratumoral H2O2 into O2, which enhanced the effect of HPTT and ST. Due to the coated HA, UMIGH could target the high expressed CD44 in CT26 tumor cells. The active targeting and NPs-associated passive targeting promoted the uptake of nanoparticles. Furthermore, ICG encapsulated in UMIGH NPs could also accurately image tumors. This synergistic treatment strategy of HPTT and ST exhibited an excellent anti-proliferation effect on colon cancer cells in vitro and mouse xenograft model in vivo, which might bring an informatic strategy for future investigations.

Near-Infrared-II Plasmonic Trienzyme-Integrated Metal-Organic Frameworks with High-Efficiency Enzyme Cascades for Synergistic Trimodal Oncotherapy.

Natural enzyme-based catalytic cascades hold great promise for cancer therapy, but their clinical utility is greatly hindered by the loss of their functions during in vivo delivery. Herein, a plasmonic trienzyme-integrated metal-organic framework (plasEnMOF) nanoplatform with high-efficiency enzyme cascades is reported for synergistic starvation, chemodynamic, and plasmonic hyperthermia trimodal therapy of hypoxic tumors. These plasEnMOFs are created with encapsulation of near-infrared-II (NIR-II) plasmonic Au nanorods and natural enzymes-catalase (CAT), glucose oxidase (GOx), and horseradish peroxidase (HRP) within zeolitic imidazolate framework-8 (ZIF-8) MOFs. As a trienzyme cascade system, the plasEnMOFs effectively deplete intratumoral glucose and generate toxic reactive oxygen species (ROS) for starvation therapy and chemodynamic therapy (CDT) combined with the plasmonic hyperthermia therapy (PHT). The enhanced glucose consumption and ROS generation by the NIR-II plasmonic photothermal effect are also demonstrated. The improved chemo- and thermotolerance of the encapsulated natural enzymes within the protective ZIF-8 MOFs are evidenced. With the integrated enzyme cascades and NIR-II photothermal effects, these plasEnMOFs are demonstrated with exceptional therapeutic effects on 4T1 xenograft tumors through the combined starvation/CDT/PHT therapy. This work highlights the superiority of natural enzyme cascade systems integrated in plasmonic MOFs for high-efficiency enzymatic cancer therapy.

Tumor-targeted biocatalyst with self-accelerated cascade reactions for enhanced synergistic starvation and photodynamic therapy

Combination therapy has been considered as an attractive strategy in complementary anticancer treatment. However, its therapeutic outcomes could be inhibited by the tumor microenvironment (TME) such as hypoxia and insufficient endogenous hydrogen peroxide concentration. Herein, we typically design a multilayered porous biocatalyst (USCGP) realizing cascade reactions-enhanced synergistic cancer therapy. Glucose oxidase (GOD) loaded on USCGP catalyzes glucose decomposition accompanied by regulating TME, which activates double enzyme-like catalysis of USCGP. Concurrently, the cascade reactions between GOD and cerium oxide (CeO2) not only promote nutrition consumption but also enhance the generation of hydroxyl radicals (•OH). In addition, under near-infrared (NIR) laser excitation, upconversion nanoparticles (UCNPs) in the core could convert NIR light to UV emission to trigger photocatalysis reactions of CeO2, achieving efficient spatio-temporal controllable photodynamic therapy. In particular, the modification of poly(ethylene glycol)-cyclo (Arg-Gly-Asp-d-Phe-Lys) (NH2-PEG1000-cRGDfK, abbreviated as PEG-cRGDfK) facilitates the accumulation of USCGP into tumor cells. Furthermore, USCGP could also be served as excellent contrast agent for computed tomography (CT) imaging in tumor diagnosis. Taken together, USCGP exhibits high-performance in tumor suppression with minimal side effects in vitro and in vivo, realizing additive cooperation of long-term starvation and robust photodynamic treatment strategy.

Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy

Tumor tissues need vast supply of nutrients and energy to sustain the rapid proliferation of cancer cells. Cutting off the glucose supply represents a promising cancer therapy approach. Herein, a tumor tissue-targeted enzyme nanogel (rGCP nanogel) with self-supply oxygen capability was developed. The enzyme nanogel synergistically enhanced starvation therapy and photodynamic therapy (PDT) to mitigate the rapid proliferation of cancer cells. The rGCP nanogel was fabricated by copolymerizing two monomers, porphyrin and cancer cells-targeted, Arg-Gly-Asp (RGD), onto the glucose oxidase (GOX) and catalase (CAT) surfaces. The cascade reaction within the rGCP nanogel could efficiently consume intracellular glucose catalyzed by GOX. Concurrently, CAT safely decomposed the produced H2O2 with systemic toxicity to promote oxygen generation and achieved low toxicity starvation therapy. The produced oxygen subsequently facilitated the glucose oxidation reaction and significantly enhanced the generation of cytotoxic singlet oxygen (1O2) in the presence of 660 nm light irradiation. Combining starvation therapy and PDT, the designed enzyme nanogel system presented an amplified synergic cancer therapy effect. This approach potentially paved a new way to fabricate a combinatorial therapy approach by employing cascaded catalytic nanomedicines with good tumor selectivity and efficient anti-cancer effect. Statement of significanceThe performance of starvation and photodynamic therapy (PDT) is usually suppressed by intrinsic tumorous hypoxia. Herein, an oxygen self-supplied and tumor tissue-targeted enzyme nanogel was created by copolymerization of two monomers, porphyrin and cancer cell-targeted Arg-Gly-Asp (RGD), onto the surface of glucose oxidase (GOX) and catalase (CAT), which synergistically enhanced starvation therapy and PDT. Moreover, the enzyme nanogels possessed high stability and could be synthesized straightforwardly. This anti-cancer system provides an approach for constructing a combinatorial therapy approach by employing cascaded catalytic nanomedicine with good tumor selectivity and therapeutic efficacy.

Erythrocyte Membrane-Camouflaged PCN-224 Nanocarriers Integrated with Platinum Nanoparticles and Glucose Oxidase for Enhanced Tumor Sonodynamic Therapy and Synergistic Starvation Therapy.

Sonodynamic therapy (SDT) is a promising method for tumor treatment, but self-quenching property, low loading efficiency of sonosensitizers, and hypoxia tumor microenvironment (TME) hinder the efficiency of SDT. Herein, an erythrocyte membrane (EM)-camouflaged metal-organic framework (MOF) of PCN-224 nanoparticles (NPs) integrated with platinum (Pt) NPs as well as glucose oxidase (GOx) has been developed to overcome these limits. Porphyrin-based PCN-224 NPs are synthesized as a sonosensitizer with a large amount of well-organized porphyrin molecules while simultaneously acting as the nanocarriers (NCs) for Pt NPs and GOx. When the NCs are internalized by tumor cells, Pt NPs on their surface are able to utilize endogenous hydrogen peroxide (H2O2) to produce oxygen for the relief of tumor hypoxia, thus enhancing the SDT effect. After EM cloaking, the longer circulation time can improve biocompatibility in vivo and enhance accumulation in tumor tissue. Loaded GOx is beneficial to local glucose consumption and can realize the tumor starvation therapy effect. Consequently, these multifunctional NCs show amplified synergistic therapeutic effects of tumor SDT and starvation therapy, which can efficiently inhibit the tumor growth.

Hypoxia modulation by dual-drug nanoparticles for enhanced synergistic sonodynamic and starvation therapy

BackgroundSonodynamic therapy (SDT) is an emerging non-invasive therapeutic technique. SDT-based cancer therapy strategies are presently underway, and it may be perceived as a promising approach to improve the efficiency of anti-cancer treatment. In this work, multifunctional theranostic nanoparticles (NPs) were synthesized for synergistic starvation therapy and SDT by loading glucose oxidase (GOx, termed G) and 5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (T (p-Cl) PPMnCl, termed PMnC) in Poly (lactic-co-glycolic) acid (PLGA) NPs (designated as MG@P NPs).ResultsOn account of the peroxidase-like activity of PMnC, MG@P NPs can catalyze hydrogen peroxide (H2O2) in tumor regions to produce oxygen (O2), thus enhancing synergistic therapeutic effects by accelerating the decomposition of glucose and promoting the production of cytotoxic singlet oxygen (1O2) induced by ultrasound (US) irradiation. Furthermore, the NPs can also serve as excellent photoacoustic (PA)/magnetic resonance (MR) imaging contrast agents, effectuating imaging-guided cancer treatment.ConclusionMultifunctional MG@P NPs can effectuate the synergistic amplification effect of cancer starvation therapy and SDT by hypoxia modulation, and act as contrast agents to enhance MR/PA dual-modal imaging. Consequently, MG@P NPs might be a promising nano-platform for highly efficient cancer theranostics.Graphical

Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy.

Mitochondria, as the energy factory of cells, often maintain a high redox state, and play an important role in cell growth, development and apoptosis. Therefore, the destruction of mitochondrial redox homeostasis has now become an important direction for cancer treatment. Here, we design a mitochondrial targeting composite enzyme nanogel bioreactor with a circulating supply of O2 and H2O2, which is composed of mitochondrial target triphenylphosphine (TPP), natural enzymes glucose oxidase (GOX) and catalase (CAT), and protoporphyrin IX (PpIX). The nanogel can effectively increase the stability of the natural enzymes, and its size of about 65 nm makes them close in space, which greatly improves their cascade catalytic efficiency and safety. Under the action of target TPP, the system can accurately target the mitochondria of breast cancer 4T1 cells, catalyze intracellular glucose to generate H2O2 through GOX, and H2O2 is further used as a catalytic substrate for CAT to generate O2. This O2 can not only further improve the catalytic efficiency of GOX, but also provide raw materials for the production of ROS in PDT, which can effectively destroy the mitochondria of cancer cells, thereby causing tumor cell apoptosis. Compared with GOX alone, thanks to the close spatial position of the composite enzymes, the composite enzyme nanogel can quickly consume the highly oxidative H2O2 produced by GOX, thereby showing better safety to normal cells. In addition, the composite enzyme group under light showed excellent antitumor effects by combining starvation therapy and PDT under adequate oxygen supply in animal experiments. In general, this composite enzyme nanogel system with good stability, high safety and excellent cascade catalytic efficiency opens a new way for the development of safe and efficient cancer therapeutics.

A smart nanoplatform for synergistic starvation, hypoxia-active prodrug treatment and photothermal therapy mediated by near-infrared-II light

Synergistic therapy with different treatment mechanisms is an emerging strategy to improve antitumor efficiency. Here, a diversified nanoplatform (Ag2S@MSN-TGF) is synthesized by coating mesoporous silica on Ag2S nanoparticles (NPs), followed by loading hypoxia-active prodrug (tirapazamine) insides the mesoporous silica and coating glucose oxidase (GOx) on the surface. Considering that the degree of hypoxia in tumors is not high enough, GOx is combined with hypoxia-active tirapazamine prodrug, and two important functions are realized. One is the consumption of oxygen to enhance the hypoxic environment and promote the curative effect of tirapazamine, and the other is the consumption of glucose to achieve starvation treatment. Additionally, we take the lead in using Ag2S NPs for second near-infrared (NIR-II, 1064 nm) excited photothermal therapy (PTT). The photothermal conversion efficiency (44.7%) of Ag2S@MSN-TGF is even better than that under 808 nm laser irradiation (38.2%). Finally, in vivo NIR-II fluorescence imaging well demonstrated that Ag2S@MSN-TGF can offer an obvious tracking effect for the therapeutic process. Therefore, superior to any single therapeutic mode, our designed Ag2S@MSN-TGF demonstrates an excellent tumor inhibition effect in vitro and in vivo due to synergistic starvation, hypoxia-active prodrug treatment and PTT effect, suggesting the significant prospect of NIR-II imaging guided antitumor therapy.

A Dual Functional Nanoreactor for Synergistic Starvation and Photodynamic Therapy.

The combination of photodynamic therapy (PDT) and enzyme therapy is a highly desirable approach in malignant tumor therapies as it takes advantage of the spatial-controlled PDT and the effective enzyme-catalyzed bioreactions. However, it is a challenge to co-encapsulate hydrophilic enzymes and hydrophobic photosensitizers, and these two agents often interfere with each other. In this work, a protocell-like nanoreactor (GOx-MSN@MnPc-LP) has been designed for synergistic starvation therapy and PDT. In this nanoreactor, the hydrophilic glucose oxidase (GOx) is loaded in the pore of mesoporous silica nanoparticles (MSNs), while the hydrophobic manganese phthaleincyanide (MnPc) is loaded in the membrane layer of liposome. This spatial separation of two payloads protects GOx and MnPc from the cellular environment and avoids interference with each other. GOx catalyzes the oxidation of glucose, which generates hydrogen peroxide and gluconic acid, leading to the starvation therapy via glucose consumption in cancer cells, as well as the disruption of cellular redox balance. MnPc produces cytotoxic singlet oxygen under 730 nm laser irradiation, achieving PDT. The antitumor effects of the nanoreactor have been verified on tumor cells and tumor-bearing mice models. GOx-MSN@MnPc-LP efficiently inhibits tumor growth in vivo with a single treatment, indicating the robust synergy of starvation therapy and PDT treatment. This work also offers a versatile strategy for delivering hydrophilic enzymes and hydrophobic photosensitizers using a protocell-like nanoreactor for effective cancer treatment.