Controlled decoration of nanoceria on the surface of MoS2nanoflowers to improve the biodegradability and biocompatibility inDrosophila melanogastermodel.

In recent years, nanozymes based on two-dimensional (2D) nanomaterials have been receiving great interest for cancer photothermal therapy. 2D materials decorated with nanoparticles (NPs) on their surface are advantageous over conventional NPs and 2D material based systems because of their ability to synergistically improve the unique properties of both NPs and 2D materials. In this work, we report a nanozyme based on flower-like MoS2nanoflakes (NFs) by decorating their flower petals with NCeO2using polyethylenimine (PEI) as a linker molecule. A detailed investigation on toxicity, biocompatibility and degradation behavior of fabricated nanozymes in wild-typeDrosophila melanogastermodel revealed that there were no significant effects on the larval size, morphology, larval length, breadth and no time delay in changing larvae to the third instar stage at 7-10 d for MoS2NFs before and after NCeO2decoration. The muscle contraction and locomotion behavior of third instar larvae exhibited high distance coverage for NCeO2decorated MoS2NFs when compared to bare MoS2NFs and control groups. Notably, the MoS2and NCeO2-PEI-MoS2NFs treated groups at 100µg ml-1covered a distance of 38.2 mm (19.4% increase when compared with control) and 49.88 mm (no change when compared with control), respectively. High-resolution transmission electron microscopy investigations on the new born fly gut showed that the NCeO2decoration improved the degradation rate of MoS2NFs. Hence, nanozymes reported here have huge potential in various fields ranging from biosensing, cancer therapy and theranostics to tissue engineering and the treatment of Alzheimer's disease and retinal therapy.

Rational Design of Surface-State Controlled Multicolor Cross-Linked Carbon Dots with Distinct Photoluminescence and Cellular Uptake Properties.

We disclose for the first time a facile synthetic methodology for the preparation of multicolor carbon dots (CDs) from a single source barring any chromatographic separations. This was achieved via sequential intraparticle cross-linking of surface abundant carboxylic acid groups on the CDs synthesized from a precursor to control their photoluminescence (PL) spectra as well as affect their degree of cellular internalization in cancer cells. The change in PL spectra with sequential cross-linking was projected by theoretical density functional theory (DFT) studies and validated by multiple characterization tools such as X-ray photoelectron spectroscopy (XPS), PL spectroscopy, ninhydrin assay, etc. The variation in cellular internalization of these cross-linked CDs was demonstrated using inhibitor assays, confocal microscopy, and flow cytometry. We supplemented our findings with high-resolution dark-field imaging to visualize and confirm the colocalization of these CDs into distinct intracellular compartments. Finally, to prove the surface-state controlled PL mechanisms of these cross-linked CDs, we fabricated a triple-channel sensor array for the identification of different analytes including metal ions and biologically relevant proteins.

A molybdenum oxide-based degradable nanosheet for combined chemo-photothermal therapy to improve tumor immunosuppression and suppress distant tumors and lung metastases.

Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.

Functionalization of filled radioactive multi-walled carbon nanocapsules by arylation reaction for in vivo delivery of radio-therapy.

Functionalized multi-walled carbon nanotubes (MWCNTs) containing radioactive salts are proposed as a potential system for radioactivity delivery. MWCNTs are loaded with isotopically enriched 152-samarium chloride (152SmCl3), the ends of the MWCNTs are sealed by high temperature treatment, and the encapsulated 152Sm is neutron activated to radioactive 153Sm. The external walls of the radioactive nanocapsules are functionalized through arylation reaction, to introduce hydrophilic chains and increase the water dispersibility of CNTs. The organ biodistribution profiles of the nanocapsules up to 24 h are assessed in naïve mice and different tumor models in vivo. By quantitative γ-counting, 153SmCl3@MWCNTs-NH2 exhibite high accumulation in organs without leakage of the internal radioactive material to the bloodstream. In the treated mice, highest uptake is detected in the lung followed by the liver and spleen. Presence of tumors in brain or lung does not increase percentage accumulation of 153SmCl3@MWCNTs-NH2 in the respective organs, suggesting the absence of the enhanced permeation and retention effect. This study presents a chemical functionalization protocol that is rapid (∼one hour) and can be applied to filled radioactive multi-walled carbon nanocapsules to improve their water dispersibility for systemic administration for their use in targeted radiotherapy.

Evaluation of Therapeutic Collagen-Based Biomaterials in the Infarcted Mouse Heart by Extracellular Matrix Targeted MALDI Imaging Mass Spectrometry.

The goal of this study was to develop strategies to localize human collagen-based hydrogels within an infarcted mouse heart, as well as analyze its impact on endogenous extracellular matrix (ECM) remodeling. Collagen is a natural polymer that is abundantly used in bioengineered hydrogels because of its biocompatibility, cell permeability, and biodegradability. However, without the use of tagging techniques, collagen peptides derived from hydrogels can be difficult to differentiate from the endogenous ECM within tissues. Imaging mass spectrometry is a robust tool capable of visualizing synthetic and natural polymeric molecular structures yet is largely underutilized in the field of biomaterials outside of surface characterization. In this study, our group leveraged a recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) technique to enzymatically target collagen and other ECM peptides within the tissue microenvironment that are both endogenous and hydrogel-derived. Using a multimodal approach of fluorescence microscopy and ECM-IMS techniques, we were able to visualize and relatively quantify significantly abundant collagen peptides in an infarcted mouse heart that were localized to regions of therapeutic hydrogel injection sites. On-tissue MALDI MS/MS was used to putatively identify sites of collagen peptide hydroxyproline site occupancy, a post-translational modification that is critical in collagen triple helical stability. Additionally, the technique could putatively identify over 35 endogenously expressed ECM peptides that were expressed in hydrogel-injected mouse hearts. Our findings show evidence for the use of MALDI-IMS in assessing the therapeutic application of collagen-based biomaterials.

Paramagnetic Mn8Fe4-co-Polystyrene Nanobeads as a Potential T1-T2 Multimodal Magnetic Resonance Imaging Contrast Agent with In Vivo Studies.

In developing a cluster-nanocarrier design, as a magnetic resonance imaging contrast agent, we have investigated the enhanced relaxivity of a manganese and iron-oxo cluster grafted within a porous polystyrene nanobead with increased relaxivity due to a higher surface area. The synthesis of the cluster-nanocarrier for the cluster Mn8Fe4O12(O2CC6H4CH═CH2)16(H2O)4, cross-linked with polystyrene (the nanocarrier), under miniemulsion conditions is described. By including a branched hydrophobe, iso-octane, the resulting nanobeads are porous and ∼70 nm in diameter. The increased surface area of the nanobeads compared to nonporous nanobeads leads to an enhancement in relaxivity; r1 increases from 3.8 to 5.2 ± 0.1 mM-1 s-1, and r2 increases from 11.9 to 50.1 ± 4.8 mM-1 s-1, at 9.4 teslas, strengthening the potential for T1 and T2 imaging. Several metrics were used to assess stability, and the porosity produced no reduction in metal stability. Synchrotron X-ray fluorescence microscopy was used to demonstrate that the nanobeads remain intact in vivo. In depth, physicochemical characteristics were determined, including extensive pharmacokinetics, in vivo imaging, and systemic biodistribution analysis.

Synthesis, Characterization and Evaluation of Peptide Nanostructures for Biomedical Applications.

There is a challenging need for the development of new alternative nanostructures that can allow the coupling and/or encapsulation of therapeutic/diagnostic molecules while reducing their toxicity and improving their circulation and in-vivo targeting. Among the new materials using natural building blocks, peptides have attracted significant interest because of their simple structure, relative chemical and physical stability, diversity of sequences and forms, their easy functionalization with (bio)molecules and the possibility of synthesizing them in large quantities. A number of them have the ability to self-assemble into nanotubes, -spheres, -vesicles or -rods under mild conditions, which opens up new applications in biology and nanomedicine due to their intrinsic biocompatibility and biodegradability as well as their surface chemical reactivity via amino- and carboxyl groups. In order to obtain nanostructures suitable for biomedical applications, the structure, size, shape and surface chemistry of these nanoplatforms must be optimized. These properties depend directly on the nature and sequence of the amino acids that constitute them. It is therefore essential to control the order in which the amino acids are introduced during the synthesis of short peptide chains and to evaluate their in-vitro and in-vivo physico-chemical properties before testing them for biomedical applications. This review therefore focuses on the synthesis, functionalization and characterization of peptide sequences that can self-assemble to form nanostructures. The synthesis in batch or with new continuous flow and microflow techniques will be described and compared in terms of amino acids sequence, purification processes, functionalization or encapsulation of targeting ligands, imaging probes as well as therapeutic molecules. Their chemical and biological characterization will be presented to evaluate their purity, toxicity, biocompatibility and biodistribution, and some therapeutic properties in vitro and in vivo. Finally, their main applications in the biomedical field will be presented so as to highlight their importance and advantages over classical nanostructures.

Biocompatibility and biodegradability of metal organic frameworks for biomedical applications.

Metal organic frameworks (MOFs) are a unique class of smart hybrid materials that have recently attracted significant interest for catalysis, separation and biomedical applications. Different strategies have been developed to overcome the limitations of MOFs for bio-applications in order to produce a system with high biocompatibility and biodegradability. In this review, we outline the chemical and physical factors that dictate the biocompatibility and biodegradability characteristics of MOFs including the nature of the metal ions and organic ligands, size, surface properties and colloidal stability. This review includes the in vitro biodegradation and in vivo biodistribution studies of MOFs to better understand their pharmacokinetics, organ toxicity and immune response. Such studies can guide the design of future bio-friendly systems that bring us closer to safely translating these platforms into the pharmaceutical consumer market.

Synthesis, characterization, and evaluation of curcumin-loaded endodontic reparative material.

Curcumin (CUR) is an ancient therapeutic agent with remarkable antimicrobial and anti-inflammatory properties. The purpose of the current study was to synthesize and evaluate a curcumin-based reparative endodontic material to reduce infection and inflammation besides the induction of mineralization during the healing of the dentin-pulp complex. Poly-ɛ-caprolactone (PCL)/gelatin (Gel)/CUR scaffold was synthesized and assessed by scanning electron microscopy, Fourier transform infrared spectroscopy, and thermo-gravimetric analysis (TGA). Agar diffusion test was performed against E. coli, A. baumannii, P. aeruginosa, S. aureus, E. faecalis, and S. mutans. Moreover, proliferative, antioxidative, anti-inflammatory, and calcification properties of these scaffolds on human dental pulp stem cells (hDPSCs) were evaluated. The results showed that PCL/Gel/CUR scaffold had antibacterial effects. Also, these CUR-based scaffolds had significant inhibitory effects on the expression of tumor necrosis factor α and DCF from inflamed hDPSCs (p < 0.05). Moreover, the induction of mineralization in hDPSCs significantly increased after seeding on CUR-based scaffolds (p < 0.05). Based on these findings, the investigated CUR-loaded material was fabricated successfully and provided an appropriate structure for the attachment and proliferation of hDPSCs. It was found that these scaffolds had antimicrobial, antioxidant, and anti-inflammatory characteristics and could induce mineralization in hDPSCs, which is essential for healing and repairing the injured dentin-pulp complex.

Evaluation of the genotoxic and cytotoxic effects of exposure to the herbicide 2,4-dichlorophenoxyacetic acid in Astyanax lacustris (Pisces, Characidae) and the potential for its removal from contaminated water using a biosorbent.

The genotoxic and cytotoxic effects of 2,4-dichlorophenoxyacetic acid (2,4-D) on specimens of Astyanax lacustris were evaluated using different biomarkers. Additionally, this study evaluated the efficiency of an activated carbon filter made from the husks green coconut, which was used as a biosorbent to remove 2,4-D dissolved in the water, and the potential effectiveness of this procedure for the reduction of the toxic effects of this compound on A. lacustris. Three sublethal concentrations of 2,4-D (10, 20, and 40 mg L-1) were tested over 24, 48, and 72 h, and their effects on Astyanax lacustris were evaluated using chromosomal aberration test, the mitotic index, the frequency of micronuclei and nuclear alterations, and the comet assay. Exposure to 2,4-D increased the frequency of chromosomal aberrations, reduced the mitotic index, and caused significant levels of nuclear modification in some of the treatments, in comparison with the negative control. The comet assay revealed DNA damage (classes 1-3) at all 2,4-D concentrations, reaching significant levels in the 20 mg L-1 (48 h) and 40 mg L-1 (72 h) treatments. The coconut husk biosorbent was highly effective for the removal of 2,4-D and the fish exposed to the water decontaminated by this filter had low levels of cellular alteration. The findings of the present study demonstrated, for the first time, the genotoxic and cytotoxic effects of 2,4-D in Astyanax lacustris, as well as suggests the potential application of a biosorbent for the effective decontamination of water contaminated with pesticides.

Nerve conduit based on HAP/PDLLA/PRGD for peripheral nerve regeneration with sustained release of valproic acid.

The nerve conduits have been developed for nerve defect repair. However, no artificial conduits have obtained comparable results to autografts to bridge the large gaps. A possible reason for this poor performance may be a lack of sustainable neurotrophic support for axonal regrowth. Previous studies suggested nanocomposite conduits can be used as a carrier for valproic acid (VPA), a common drug that can produce effects similar to the neurotrophic factors. Here, we developed the novel bioabsorbable conduits based on hydroxyapatite/poly d-l-lactic acid (PDLLA)/poly{(lactic acid)-co-[(glycolic acid)-alt-(l-lysine)]} with sustained release of VPA. Firstly, the sustained release of VPA in this conduit was examined by high-performance liquid chromatography. Then Schwann cells were treated with the conduit extracts. The cell metabolic activity and proliferation were assayed by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide and bromodeoxyuridine staining. A 10-mm segment of rat sciatic nerve was resected and then repaired, respectively, using the VPA conduit (Group A), the PDLLA conduit (Group B), or the autografts (Group C). Nerve conduction velocities (NCVs), compound muscle action potentials (CMAPs), and histological staining were assayed following the surgery. The cell metabolic activity and proliferation were significantly increased (p < .05) by the extracts from VPA-conduit extract compared to others. NCVs and CMAPs were significantly higher in Groups A and C than Group B (p < .05). The nerve density of Groups A and C was higher than Group B. There was no significant difference between Groups A and C. Taken together, this study suggested the sustained-release VPA conduit promoted peripheral nerve regeneration that was comparable to the autografts. It holds potential for future use in nerve regeneration.

Hemostatic performance of chitosan-based hydrogel and its study on biodistribution and biodegradability in rats.

Hemostasis is of great significance regardless of the smooth operation or postoperative recovery. Therefore, it is urgent to develop a hemostatic material with excellent biodegradability and biocompatibility. It is well known that both carboxymethyl chitosan and hyaluronic acid with biodegradability and biocompatibility have wound healing promoting property. Here, a degradable chitosan-based hydrogel was prepared based on carboxymethyl chitosan and cross-linked by oxidized hyaluronic acid. The hemostatic performance of the hydrogel in rat liver resection injury was evaluated which results showed that the hydrogel exhibited comparable hemostatic properties compared with Fibrin Sealant. In addition, the hydrogel proved to be rapidly absorbed by the body without significant accumulation in vivo, demonstrating good biodegradability and biocompatibility. The overall results suggested the hydrogel will be a promising hemostatic hydrogel for controlling bleeding.

Chitosan-based systems aimed at local application for vaginal infections.

Vaginal administration is a promising route for the local treatment of infectious vaginal diseases since it can bypass the first-pass metabolism, drug interactions, and adverse effects. However, the commercial products currently available for topical vulvovaginal treatment have low acceptability and do not adequately explore this route. Mucoadhesive systems can optimize the efficacy of drugs administered by this route to increase the retention time of the drug in the vaginal environment. Several polymers are used to develop mucoadhesive systems, among them chitosan, a natural polymer that is highly biocompatible and technologically versatile. Thus, the present review aimed to analyze the studies that used chitosan to develop mucoadhesive systems for the treatment of local vaginal infections. These studies demonstrated that chitosan as a component of mucoadhesive drug delivery systems (DDS) is a promising device for the treatment of vaginal infectious diseases, due to the intrinsic antimicrobial activity of this biopolymer and because it does not interfere with the effectiveness of the drugs used for the treatment.

PEG-α-CD/AM/liposome @amoxicillin double network hydrogel wound dressing-Multiple barriers for long-term drug release.

Wound infection and poor wound healing are the major challenges of wound treatment. Antibiotic drug treatment is the effective way to inhibit wound infection. It is necessary to achieve sustained release of antibiotics to get a longer treatment for wound infection. The double network hydrogels based on liposome, polyethylene glycol (PEG), α- cyclodextrin (α-CD) and acrylamide (AM) were developed, in which liposome acts as amoxicillin repository. Because the drug would release from the multiple barriers including two cavities of liposome and α-CD, as well as polyethylene glycol -α- cyclodextrin/acrylamide (PEG-CD/AM) double network, the PEG-α-CD/AM/liposome @amoxicillin double network hydrogels could achieve sustained drug release. The drug release assay showed that the dressing could release amoxicillin continuously until 12 days, than that of 8th day for single-network hydrogel releasing. The antibacterial ratio of the hydrogel could reach above 80%. What's more, the hydrogels present adjustable mechanical strength by changing the ratio of the components. The swelling ratio proved that the hydrogel had potential ability to absorb wound exudates. The cytotoxicity test of the hydrogels demonstrated excellent biocompatibility. These results indicated that this study can provide a new thought for antibacterial wound dressing and has a broad application prospect.

An overview of chitosan and its application in infectious diseases.

Infectious diseases, such as the coronavirus disease-19, SARS virus, Ebola virus, and AIDS, threaten the health of human beings globally. New viruses, drug-resistant bacteria, and fungi continue to challenge the human efficacious drug bank. Researchers have developed a variety of new antiviral and antibacterial drugs in response to the infectious disease crisis. Meanwhile, the development of functional materials has also improved therapeutic outcomes. As a natural material, chitosan possesses good biocompatibility, bioactivity, and biosafety. It has been proven that the cooperation between chitosan and traditional medicine greatly improves the ability of anti-infection. This review summarized the application and design considerations of chitosan-composed systems for the treatment of infectious diseases, looking forward to providing the idea of infectious disease therapy.

Redox-triggered aggregation of ESIONPs with switchable T1 to T2 contrast effect for T2-weighted magnetic resonance imaging.

Magnetic resonance imaging (MRI) contrast agents (CAs) have drawn increasing attention in cancer diagnosis. However, since the signals they generate are always "on" and may bring interfering background signals to the region of interest, their selectivity and sensitivity need further improvement. Herein, extremely small iron oxide nanoparticles (ESIONPs) conjugated through a disulfide bond with polyethylene glycol (PEG) that is terminally modified with folic acid (FA), namely ESIONPs-s-s-PEG-FA, were designed and synthesized to target tumor tissues and selectively activate the T2 MRI contrast effect in the reducing environment of tumor cells. Due to the breakage of disulfide bonds by the high glutathione (GSH) concentration in tumor cells, the hydrophilic PEG chains detached from the surface of ESIONPs, which led to the aggregation of ESIONPs and the activation of the T2 contrast effect. In vitro results showed that ESIONPs-s-s-PEG-FA could effectively target tumors to assemble in the reductive environment and switch from a T1 contrast agent (CA) to a T2 one. Furthermore, MRI in tumor-bearing mice also indicated the obvious targeting capacity and the "turn on" of the T2 contrast effect. In addition, the results of the biosafety assay suggest that the tumor-targeted T1/T2 switchable CA is equipped with favorable biocompatibility for cancer diagnosis.

Long-term in vitro degradation and in vivo evaluation of resorbable bioceramics.

An essential criterion for the selection of resorbable bioceramics is their ability to degrade inside human body within a reasonable time frame. Furthermore, if the bioceramic can release beneficial ions, such as strontium, as it degrades, recovery time might be shortened. The present study demonstrates that strontium-containing calcium sulfate (Sr,Ca)SO4 can fulfill these criteria. A long-term in vitro degradation analysis for 12 weeks using sintered (Sr,Ca)SO4 discs in phosphate buffered solution (PBS) was conducted. The sintered (Sr,Ca)SO4 disc was then implanted into defects in the distal femur of rats. The degradation rate of (Sr,Ca)SO4 discs showed a strong dependence on the Sr content. Similar results were observed between the long-term in vitro degradation analysis and the in vivo evaluation. The sintered (3.8%Sr,Ca)SO4 disc lost more than 80% of its initial weight after soaking in PBS with shaking at 37 °C for 12 weeks. After 12 weeks in vivo, the remaining volume of the (3.8%Sr,Ca)SO4 disc within the bone defect was ~25%. Over the same time period, new bone was formed at a relative volume of 40%. This study demonstrates the potential of (Sr,Ca)SO4 bioceramic, and the benefits of using a long-term degradation test during the evaluation of resorbable bioceramics.

Fluorophore Selection and Incorporation Contribute to Permeation and Distribution Behaviors of Hyperbranched Polymers in Multi-Cellular Tumor Spheroids and Xenograft Tumor Models.

Improving our understanding of how design choices in materials synthesis impact biological outcomes is of critical importance in the development of nanomedicines. Here, we show that fluorophore labeling of polymer nanomedicine candidates significantly alters their transport and cell association in multi-cellular tumor spheroids and their penetration in breast cancer xenografts, dependent on the type of the fluorophore and their positioning within the macromolecular structure. These data show the critical importance of the biomaterials structure and architecture in their tissue distribution and intracellular trafficking, which in turn govern their potential therapeutic efficacy. The broader implication of these findings suggests that when developing materials for medical applications, great care should be taken early on in the design process as relatively simple choices may have downstream impacts that could potentially skew preclinical biology data.

Post-loading of proangiogenic growth factors in PLGA microspheres.

Active self-encapsulation (ASE) is a recently developed post-loading method based on absorption of (positively charged) proteins in microporous PLGA microspheres loaded with negatively charged polysaccharides (trapping agents). The aim of this study was to investigate ASE for simultaneous loading and controlled release of multiple growth factors. For this purpose, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factor (IGF) were loaded in microspheres containing high molecular weight dextran sulfate (HDS) as trapping agent; loading was performed in a concentrated growth factor solution of low ionic strength and of pH 5 under conditions at which the proteins are positively charged. Subsequent pore closure was induced by incubation of the growth factor-loaded microspheres at 42.5 °C, i.e. above the Tg of (hydrated) PLGA (~30 °C). A 1:1:1 combination of VEGF, FGF and IGF was loaded with high loading (4.3%) and loading efficiency (91%). The in vitro release kinetics and bioactivity of loaded growth factors were studied for 4 weeks using ELISA and an endothelial cell proliferation assay, respectively. While IGF was released quickly, VEGF and FGF were continuously released for 4 weeks in their bioactive form, whereby a growth factor combination had a synergistic angiogenic effect. Therefore, ASE is a suitable method for co-loading growth factors which can provide sustained release profiles of bioactive growth factors, which is attractive for vascularization of biomaterial implants.

Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy.

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.