Cascade Nanoreactor Research Articles

A multifunctional cascade nanoreactor based on Fe-driven carbon nanozymes for synergistic photothermal/chemodynamic antibacterial therapy.

Healing bacterial chronic wounds caused by hyperglycemia is of great significance to protect the physical and mental health of diabetic patients. In this context, emerging chemodynamic therapy (CDT) and photothermal therapy (PTT) with broad antibacterial spectra and high spatiotemporal controllability have flourished. However, CDT was challenged by the near-neutral pH and inadequate H2O2 surrounding the chronic wound site, while PTT showed overheating-triggered side effects (e.g., damaging the normal tissue) and poor effects on thermotolerant bacterial biofilms. Therefore, we engineered an all-in-one glucose-responsive photothermal nanozyme, GOX/MPDA/Fe@CDs, consisting of glucose oxidase (GOX), Fe-doped carbon dots (Fe@CDs), and mesoporous polydopamine (MPDA), to efficiently treat chronic diabetic wound bacterial infections and eradicate biofilms without impacting the surrounding normal tissues. Specifically, GOX/MPDA/Fe@CDs produced a local temperature (∼ 45.0°C) to enhance the permeability of the pathogenic bacterium and its biofilm upon near-infrared (NIR) 808 nm laser irradiation, which was seized to initiate endogenous high blood glucose to activate the catalytic activity of GOX on the GOX/MPDA/Fe@CD surface to achieve the simultaneous self-supplying of H2O2 and H+, cascade catalyzing •OH production via a subsequent peroxidase-mimetic activity-induced Fenton/Fenton-like reaction. As such, the in vivo diabetic wound infected with methicillin-resistant Staphylococcus aureus was effectively healed after 12.0 days of treatment. This work was expected to provide an innovative approach to the clinical treatment of bacterially infected diabetic chronic wounds. STATEMENT OF SIGNIFICANCE: An all-in-one glucose-responsive photothermal nanozyme GOX/MPDA/Fe@CDs was constructed. Cascade nanozyme GOX/MPDA/Fe@CDs self-supply H2O2 and H+ to break H2O2 and pH limits to fight bacterial infections. Synergistic chemotherapy and photothermal therapy with nanozyme GOX/MPDA/Fe@CDs accelerates healing of biofilm-infected diabetic wounds.

A Purposefully Designed pH/GSH-Responsive MnFe-Based Metal-Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo-Chemodynamic-Starvation Synergistic Therapy.

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

Bioengineered "Molecular Glue"-Mediated Tumor-Specific Cascade Nanoreactors with Self-Destruction Ability for Enhanced Precise Starvation/Chemosynergistic Tumor Therapy.

The ordered and directed functionalization of targeting elements on the surface of nanomaterials for precise tumor therapy remains a challenge. To address the above problem, herein, we adopted a materials-based synthetic biotechnology strategy to fabricate a bioengineered fusion protein of materials-binding peptides and targeting elements, which can serve as a "molecular glue" to achieve a directional and organized assembly of targeting biological macromolecules on the surface of nanocarriers. The hypoxia microenvironment of solid tumors inspired the rapid development of starvation/chemosynergistic therapy; however, the unsatisfied spatiotemporal specific performance hindered its further development in precise tumor therapy. As a proof of concept, a bioengineered fusion protein containing a dendritic mesoporous silicon (DMSN)-binding peptide, and a tumor-targeted and acidity-decomposable ferritin heavy chain 1 (FTH1), was constructed by fusion expression and further assembled on the surface of DMSN companying with the insertion of hypoxia-activated prodrug tirapazamine (TPZ) and glucose oxidase (GOX) to establish a nanoreactor for precise starvation/chemosynergistic tumor therapy. In this context, the as-prepared therapeutic nanoreactors revealed obvious tumor-specific accumulation and an endocytosis effect. Next, the acidic tumor microenvironment triggered the structural collapse of FTH1 and the subsequent release of GOX and TPZ, in which GOX-mediated catalysis cut off the nutrition supply to realize starvation therapy based on the consumption of endogenous glucose and further provided an exacerbated hypoxia environment for TPZ in situ activation to initiate tumor chemotherapy. More significantly, the presence of "molecular glue" elevated the tumor-targeting capacity of nanoreactors and further enhanced the starvation/chemosynergistic therapeutic effect remarkably, suggesting that such a strategy provided a solution for the functionality of nanomaterials and facilitated the design of novel targeting nanomedicines. Overall, this study highlights materials-binding peptides as a new type of "molecular glue" and opens new avenues for designing and exploring active biological materials for biological functions and applications.

DNAzyme-Mediated Cascade Nanoreactor for Cuproptosis-Promoted Pancreatic Cancer Synergistic Therapy.

Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper-based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu+ can release from the nanosystem. Since Cu+ having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu+ induces cuproptosis and CDT efficiently, accompanied by Cu2+ generation. Then Cu2+ can be converted into Cu+ partially by glutathione (GSH) to from a Cu+ supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn2+ form DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis.

Self-Supplying of Hydrogen Peroxide/Oxygen Based on CaO2-Co3O4 Cascade Nanoreactors for Cellular Microenvironment Regulation

Self-Supplying of Hydrogen Peroxide/Oxygen Based on CaO₂-Co₃O₄ Cascade Nanoreactors for Cellular Microenvironment Regulation

Fabrication of Biomimetic Cascade Nanoreactor Based on Covalent Organic Framework Capsule for Biosensing.

The cooperation of biocatalysis and chemocatalysis in a catalytic cascade reaction has received extensive attention in recent years, whereas its practical applications are still hampered due to the fragility of the enzymes, poor compatibility between the carriers and enzymes, and limited catalytic efficiency. Herein, a biomimetic cascade nanoreactor (GOx@COFs@Os) was presented by integrating glucose oxidase (GOx) and Os nanozyme with covalent organic framework (COF) capsule using metal-organic framework (ZIF-90) as a template. The obtained GOx@COFs@Os capsule provided a capacious microenvironment to retain the conformational freedom of GOx for maintaining its activity, wherein the enzyme activity of GOx in COF capsules was equal to 92.9% of the free enzyme and was 1.88-folds higher than that encapsulated in ZIF-90. Meanwhile, the COF capsule could protect the GOx against incompatible environments (high temperature, acid, and organic solvents), resulting in improved stability of the packaged enzymes. Moreover, the COF capsule with great pore structure significantly improved the affinity to substrates and facilitated efficient mass transfer, which achieved 2.19-folds improvement in catalytic efficiency than the free cascade system, displaying the great catalytic performance in the cascade reaction. More importantly, the biomimetic cascade capsule was successfully employed for glucose monitoring, glutathione sensing, and bisphenol S detection in the immunoassay as a proof-of-concept. Our strategy provided a new avenue in the improvement of biocatalytic cascade performance to encourage its wide applications in various fields.

Construction a starving therapy induced photothermal enhanced cascade nanoreactor for imaging guided catalytic synergistic therapy of tumor

Multienzyme cascade reaction has shown great potential in tumor therapy and photothermal was usually introduced to nanozyme to improve the catalytic efficiency which is limited by tumor microenvironment. However, it is difficult to determine the optimal treatment window in photothermal enhanced catalytic therapy. In order to solve the problem, a trackable-imaging multifunctional cascade reactor was designed with glucose oxidase (GOx) loaded bimetallic Fe/Cu-MOF-199 as core and polydopamine (PDA) as shell, with the pH/GSH targeting of the shell PDA, Fe/Cu-MOF-199/GOx@PDA can be enriched in tumor cells. With the release of GOx from the core Fe/Cu-MOF-199, the glucose in tumor can be catalyzed to supply H2O2, reduce heat resistance, and with the self-cyclic valence alteration of Fe3+/Fe2+ and Cu2+/Cu+, GSH can be constantly consumed, greatly reducing the anti-oxidation defense effect of tumor. Through the activities of catalase and peroxidase of Fe/Cu-MOF-199, O2 and hydroxyl radicals (•OH) are generated to kill cancer cells and compensate for O2 consumed in glucose catalytic reaction, respectively. Furthermore, under MRI guiding, near-infrared light excitation is performed at the optimal concentration of Fe/Cu-MOF-199/GOx@PDA in the tumor. Promoting the multienzyme activity in TME to the greatest extent. Cytotoxicity proved the selectivity, and in vivo experiments confirmed that the catalytic synergistic treatment of multienzyme cascade reaction and photothermal therapy was satisfactory. The study provides new promising ideas for designing multifunctional cascade nanoreactor for efficient cancer treatment.

Supramolecular Photothermal Cascade Nano-Reactor Enables Photothermal Effect, Cascade Reaction, and In Situ Hydrogelation for Biofilm-Associated Tooth-Extraction Wound Healing.

Due to the emergence of drug resistance in bacteria and biofilm protection, achieving a satisfactory therapeutic effect for bacteria-infected open wounds with conventional measures is problematic. Here, we construct a photothermal cascade nano-reactor (CPNC@GOx-Fe2+ ) through a supramolecular strategy through hydrogen bonding and coordination interactions between chitosan-modified palladium nano-cube (CPNC), glucose oxidase (GOx), and ferrous iron (Fe2+ ). CPNC@GOx-Fe2+ exhibits excellent photothermal effect and powers the GOx-assisted cascade reaction to generate hydroxyl radicals, enabling photothermal and chemodynamic combination therapy against bacteria and biofilms. Further proteomics, metabolomics, and all-atom simulation results indicate that the damage of hydroxyl radical to the function and structure of the cell membrane and the thermal effect enhances the fluidity and inhomogeneity of the bacterial cell membrane, resulting in the synergistic anti-bacterial effect. In the biofilm-associated tooth extraction wound model, hydroxyl radical generated from the cascade reaction process could initiate the radical polymerization process to form a hydrogel in situ for wound protection. In vivo experiments confirm synergistic anti-bacterial and wound protection can accelerate the healing of infected tooth-extraction wounds without affecting the oral commensal microbiota. This study provides a way to propose a multifunctional supramolecular system for the treatment of open wound infection. This article is protected by copyright. All rights reserved.

Confined Cascade Metabolic Reprogramming Nanoreactor for Targeted Alcohol Detoxification and Alcoholic Liver Injury Management

Alcoholic liver injury (ALI) is the leading cause of serious liver disease, whereas current treatments are mostly supportive and unable to metabolize alcohol directly. Here we report a metabolic reprogramming strategy for targeted alcohol detoxification and ALI management based on a confined cascade nanoreactor. The nanoreactor (named AA@mMOF) is designed by assembling natural enzymes of alcohol oxidase (AOx) and aldehyde dehydrogenase (ALDH) in the cavity of a mesoporous metal organic framework (mMOF) nanozyme with intrinsic catalase (CAT)-like activity. By conducting confined AOx/CAT/ALDH cascade reactions, AA@mMOF enables self-accelerated alcohol degradation (>0.5 mg·mL-1·h-1) with negligible aldehyde diffusion and accumulation, reprogramming alcohol metabolism and allowing high-efficiency detoxification. Administered to high-dose alcohol-intoxicated mice, AA@mMOF shows surprising liver targeting and accumulation performance and dramatically reduces blood alcohol concentration and rapidly reverses unconsciousness and acute liver injury to afford targeted alcoholism treatment. Moreover, AA@mMOF dramatically alleviates fat accumulation and oxidative stress in the liver of chronic alcoholism mice to block and reverse the progression of ALI. By conducting confined AOx/CAT/ALDH cascade reactions for high-efficiency alcohol metabolism reprogramming, AA@mMOF nanoreactor offers a powerful modality for targeted alcohol detoxification and ALI management. The proposed confined cascade metabolic reprogramming strategy provides a paradigm shift for the treatment of metabolic diseases.

Synergistic ferroptosis-starvation therapy for bladder cancer based on hyaluronic acid modified metal-organic frameworks.

Bladder cancer (BCa) is one of the most common malignancies of the urinary tract. Metastasis and recurrence of BCa are the leading causes of poor prognosis, and only a few patients can benefit from current first-line treatments such as chemotherapy and immunotherapy. It is urgent to develop more effective therapeutic method with low side effects. Here, a cascade nanoreactor, ZIF-8/PdCuAu/GOx@HA (ZPG@H), is proposed for starvation therapy and ferroptosis of BCa. The ZPG@H nanoreactor was constructed by co-encapsulation of PdCuAu nanoparticles and glucose oxidase into zeolitic imidazolate framework-8 (ZIF-8) modified by hyaluronic acid. The vitro results indicated that ZPG@H enhanced intracellular reactive oxygen species levels and reduced mitochondrial depolarization in the tumor microenvironment. Therefore, the integrated advantages of starvation therapy and chemodynamic therapy endow ZPG@H with a perfect ferroptosis inducing ability. This effectiveness, combined with its excellent biocompatibility and biosafety, means that ZPG@H could make a critical contribution to the development of novel BCa treatments.

A Multiple-Response Cascade Nanoreactor for Starvation and Deep Catalysis Chemodynamic Assisted Near-Infrared-II Mild Photothermal Therapy.

Photothermal therapy (PTT) is hampered by the limited capacity of light penetration, non-specific thermal diffusion damage to surrounding healthy tissues, and thermoresistance originating in heat shock proteins (HSPs). Here, a triple-respondent (triphosphate, glutathione, and pH) cascade nanoreactor was designed through the glucose consumption-induced thermal sensitization strategy. The near-infrared-II (NIR-II) photothermal reagent Bi-Au was encapsulated in a glucose oxidase-based protein-polyphenol structure with the help of the zeolitic imidazolate framework-8 (ZIF-8). The composite nanosystem possesses triple-enzyme activity (glucose oxidase, peroxidase-like, and catalase-like). On one hand, the product of hydrogen peroxide from glycolysis can be converted into reactive oxygen species and oxygen to enhance the chemodynamic therapy and alleviate the state of hypoxia in tumor cells. On the other hand, glucose consumption could down-regulate the expression level of HSPs. The heat resistance ability of cells decreased under starvation and oxidative damage states, which is beneficial to reduce the temperature required for PTT and improve the efficiency of mild PTT. The cascade nanocapsule exhibited high tumor inhibition and proposed a typical synergistic strategy for starvation, chemodynamic, and NIR-II mild photothermal therapy.

A cascade nanoreactor for enhancing sonodynamic therapy on colorectal cancer via synergistic ROS augment and autophagy blockage

The ultrasound-triggered sonodynamic therapy (SDT) with high tissue penetration, high spatiotemporal selectivity, and non-invasive advantages represents an emerging approach to eradicating deep-seated solid tumors. However, the outcomes of SDT are typically hampered by the inefficient generation of reactive oxygen species (ROS) and the activation of protective autophagy. Here, to improve the antitumor efficiency of SDT on colorectal cancer, we rationally design a cascade nanoreactor by incorporating sonosensitizer Ce6 and autophagy inhibitor chloroquine into the homologous tumor cell membrane-modified hollow polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated as CCP@HP@M). The cascade reactions of CCP@HP@M are evidenced by the results that HP exhibits superoxide dismutase-mimicking activity that converts O2·− to O2 and H2O2, and platinum nanozymes further catalyze the excess H2O2 to produce toxic ·OH and O2. CCP@HP@M effectively accumulates in the tumor cells, resulting in a remarkably enhanced SDT efficiency for eliminating the tumor cells in vitro and in vivo. Under ultrasound irradiation, CCP@HP@M effectively alleviates the hypoxic condition, enhances ROS generation, and inhibits the protective autophagy pathway, which results in stimulating apoptosis and ferroptosis in vitro and in vivo. The RNA-seq analyses also confirmed apoptosis and ferroptosis pathways involved in the CCP@HP@M treatment. This cascade nanoreactor will provide a promising strategy for augmenting SDT eradication against tumors by modulation of ROS and autophagy.

Mitochondrial-mimicking nanozyme-catalyzed cascade reactions for aging attenuation

Population aging is an increasingly aggravated public issue worldwide. Nanomaterials with enzyme-like activities are recognized as potentially important nanomedicines, yet how to leverage their in vivo performance for anti-aging therapy is still challenging. Here inspired by vital roles of mitochondrial respiratory chain complex enzymes on bioenergy generation and longevity, we reported a Pd based single-atom nanozyme (Pd@PPy/GO) as cascade nanoreactors to improve mitochondrial activities for aging attenuation. By mimicking NADH oxidase (NOX) and Cytochrome c oxidase (CcO), the nanozyme can catalyze the cascade reactions on mitochondrial respiratory chain and produce NAD+ without any external stimuli. At both Caenorhabditis elegans (C. elegans) and cell levels, we verified that nanozyme treatment could boost the mitochondrial function and abundance. More importantly, the nanozyme showed excellent anti-aging and neuroprotective effect. Mechanically, the activated mitochondrial unfolded protein response (UPRmt) pathway plays a vital role in its anti-aging effect. Together, this work paves a way for nanocatalytic anti-aging therapy by rationally designing a simple and powerful nanozymes with dual-enzymatic activities.

Tumor microenvironment (TME)-modulating nanoreactor for multiply enhanced chemodynamic therapy synergized with chemotherapy, starvation, and photothermal therapy.

The combination of chemotherapy (CT) and chemodynamic therapy (CDT) via nanoscale drug delivery systems has great potential for tumor therapy. Nevertheless, the low intracellular H2O2 and high reductive glutathione (GSH) levels, as well as the mildly acidic conditions (pH 5.8-6.8) of the tumor microenvironment (TME) still limit their further applications. To tackle these problems, a TME-modulating nanoreactor (denoted as Fe3O4-DOX@PDA-GOx@HA, FDPGH) was developed through a simple and practicable method to achieve multiply enhanced CDT synergized with CT, starvation therapy (ST), and photothermal therapy (PTT). Upon cellular uptake, the hyaluronic acid (HA) and PDA shells rapidly collapsed to release Fe3O4, glucose oxidase (GOx) and doxorubicin (DOX), and the overexpressed GSH could promote the reduction of Fe3+ to Fe2+, resulting in CDT activation. GOx-driven oxidation reaction not only produced H2O2 for enhanced CDT, but also killed tumor cells by initiating ST. In addition, the acid amplification caused by gluconic acid production in turn accelerated the degradation of FDPGH, promoting the Fenton reaction to enhance CDT. Most importantly, the nanoreactor had excellent photothermal performance to achieve PTT and PTT-enhanced CDT with the release of DOX into tumor tissue to achieve enhanced CT. This novel cascade nanoreactor with TME-modulating capability is intended to provide further inspiration for multimodal treatment paradigms.

A small pore black TiO2/-large pore Fe3O4 cascade nanoreactor for chemodynamic/photothermal synergetic tumour therapy.

Various unique spatial structures are often found in the enzymes of biological systems. From the consideration of bionics, it is challenging but meaningful to design nanozymes with distinctive structures to enhance their bioactivities. To explore the relationship between the structure and activity of nanozymes, in this work, a special structural nanoreactor, namely small pore black TiO2 coated/doped large pore Fe3O4 (TiO2/-Fe3O4) loaded with lactate oxidase (LOD), was constructed for chemodynamic and photothermal synergistic therapy. Specifically, LOD loaded on the surface of the TiO2/-Fe3O4 nanozyme alleviates the low level of H2O2 in the tumour microenvironment (TME); the black TiO2 shell with multiple pinhole channels and a large specific surface area not only facilitates LOD loading, but also enhances the affinity of the nanozyme for H2O2; H2O2 is continuously enriched on the surface of the TiO2/-Fe3O4 nanozyme and transmitted to mesoporous Fe3O4, in turn efficiently producing abundant toxic hydroxyl radicals (˙OH) for chemodynamic therapy. Meanwhile, the TiO2/-Fe3O4 nanozyme under 1120 nm laser irradiation has excellent photothermal conversion efficiency (η = 41.9%), and further accelerates the production of ˙OH for amplifying the chemodynamic therapy efficiency. This self-cascading, special structure nanozyme provides a novel strategy for application in highly efficient tumour synergetic therapy.

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.

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.

Photodynamic Hydrogen-Bonded Biohybrid Framework: A Photobiocatalytic Cascade Nanoreactor for Accelerating Diabetic Wound Therapy.

A diabetic wound causes thousands of infections or deaths around the world each year, and its healing remains a critical challenge because of the ease of multidrug-resistant (MDR) bacterial infection, as well as the intrinsic hyperglycemic and hypoxia microenvironment that inhibits the therapeutic efficiency. Herein, we pioneer the design of a photobiocatalytic cascade nanoreactor via spatially organizing the biocatalysts and photocatalysts utilizing a hydrogen-bonded organic framework (HOF) scaffold for diabetic wound therapy. The HOF scaffold enables it to disperse and stabilize the host cargos, and the formed long-range-ordered mesochannels also facilitate the mass transfer that enhances the cascade activity. This integrated HOF nanoreactor allows the continuous conversion of overexpressed glucose and H2O2 into toxic reactive oxygen species by the photobiocatalytic cascade. As a result, it readily reverses the microenvironment of the diabetes wound and exhibits an extraordinary capacity for wound healing through synergistic photodynamic therapy. This work describes the first example of constructing an all-in-one HOF bioreactor for antimicrobial diabetes wound treatment and showcases the promise of combined biocatalysis and photocatalysis achieved by using an HOF scaffold in biomedicine applications.

Robust Dual Enzyme Cascade-Catalytic Cholesterol Depletion for Reverse Tumor Multidrug Resistance.

Although combination drugs and P-glycoprotein inhibitors are the main methods to solve multidrug resistance, these methods ignore the pathological structure of drug-resistant cells and extremely limit curative effect. Herein, a new paradigm of reversing multidrug resistance with abnormal expression of cholesterol as the target is proposed, which uses the cascade catalysis of "natural enzyme" cholesterol oxidase (COD) and "nanoenzyme" Cu2+ -modified zirconium-based metal-organic framework (ZrMOF(Cu)) to convert cholesterol into the highly cytotoxic hydroxyl radicals. The doxorubicin (DOX)-loaded nanoparticles (DOX@COD-MOF) can significantly reduce the cholesterol content of cancer cells via COD, which decrease the rigidity of drug resistant cancer cell membranes and restore the sensitivity of multidrug-resistant cells to DOX. Afterward, DOX@COD-MOF is encapsulated by cancer cell membranes (CCM) to construct a bionic "dual enzyme catalytic cascade nanoreactor" (DOX@COD-MOF@CCM). Such a rational design presents a preferential accumulation tendency to tumor sites due to the homologous targeting mechanism of CCM, and affords 94.4% in tumor growth suppression without systemic toxicity in vivo. This work aims to achieve the therapeutic purpose of high efficiency and low toxicity. It has the characteristics of "converting enemy into friend, " and opens up a promising way for effectively reversing multidrug resistance of tumors.

Collagen-anchored cascade nanoreactors with prolonged intratumoral retention for combined cancer starvation and chemotherapy

Cancer starvation therapy mediated by glucose oxidase (GOx) has attracted considerable attention for treating advanced tumors. However, the severe systemic toxicity and poor stability of GOx limit the clinical translation of this strategy. To overcome these limitations, we construct collagen-anchored hollow nanoreactors to enhance intratumoral retention and biosafety of enzymes. Specifically, GOx and catalase (CAT) are encapsulated in tannic acid/poly(ethylenimine) crosslinked hollow nanocapsules ((GOx + CAT)@PTP) using a sacrificial templating method. Then doxorubicin hydrochloride (DOX) is absorbed on the surface of the (GOx + CAT)@PTP nanoreactors to form (GOx + CAT)@PTP@DOX nanoreactors. Because of the high affinity between the tannic acid in the nanoreactors and collagen in the tumor stroma, the nanoreactors greatly prolong the retention of GOx and CAT and reduce the systemic toxicity of GOx by preventing its escape. The catalytic cascade initiated by GOx and CAT realizes oxygen self-supply, facilitates glucose consumption, and lowers the pH in the tumor microenvironment, which induces DOX release. As a result, the (GOx + CAT)@PTP@DOX nanoreactors show excellent antitumor efficacy by combining starvation therapy and chemotherapy. Since collagen is abundant in various tissues, such as tumors, dermis, and tendons, our findings may facilitate the development of new enzyme delivery platforms with enhanced delivery efficiency, retention, and therapeutic efficacy.