Human Adipose Tissue Lysate-Based Hydrogel for Lasting Immunomodulation to Effectively Improve Spinal Cord Injury Repair.

The long-term inflammatory microenvironment is one of the main obstacles to inhibit acute spinal cord injury (SCI) repair. The natural adipose tissue-derived extracellular matrix hydrogel shows effective anti-inflammatory regulation because of its unique protein components. However, the rapid degradation rate and removal of functional proteins during the decellularization process impair the lasting anti-inflammation function of the adipose tissue-derived hydrogel. To address this problem, adipose tissue lysate provides an effective way for SCI repair due to its abundance of anti-inflammatory and nerve regeneration-related proteins. Thereby, human adipose tissue lysate-based hydrogel (HATLH) with an appropriate degradation rate is developed, which aims to in situ long-term recruit and induce anti-inflammatory M2 macrophages through sustainedly released proteins. HATLH can recruit and polarize M2 macrophages while inhibiting pro-inflammatory M1 macrophages regardless of human or mouse-originated. The axonal growth of neuronal cells also can be effectively improved by HATLH and HATLH-induced M2 macrophages. In vivo experiments reveal that HATLH promotes endogenous M2 macrophages infiltration in large numbers (3.5 × 105/100 µL hydrogel) and maintains a long duration for over a month. In a mouse SCI model, HATLH significantly inhibits local inflammatory response, improves neuron and oligodendrocyte differentiation, enhances axonal growth and remyelination, as well as accelerates neurological function restoration.

An "All-in-One" Strategy to Reconstruct Temporomandibular Joint Osteoarthritic Microenvironment Using γ-Fe2O3@TA@ALN Nanoparticles.

Current clinical strategies for the treatment of temporomandibular joint osteoarthritis (TMJOA) primarily target cartilage biology, overlooking the synergetic effect of various cells and inorganic components in shaping the arthritic microenvironment, thereby impeding the effectiveness of existing therapeutic options for TMJOA. Here, γ-Fe2O3@TA@ALN magnetic nanoparticles (γ-Fe2O3@TA@ALN MNPs) composed of γ-Fe2O3, tannic acid (TA), and alendronate sodium (ALN) are engineered to reconstruct the osteoarthritic microenvironment and mitigate TMJOA progression. γ-Fe2O3@TA@ALN MNPs can promote chondrocytes' proliferation, facilitate chondrogenesis and anisotropic organization, enhance lubrication and reduce cartilage wear, and encourage cell movement. Magnetic-responsive γ-Fe2O3@TA@ALN MNPs also exhibit pH sensitivity, which undergoes decomposition within acidic environment to release ALN on demand. Under a 0.2 T static magnetic field, γ-Fe2O3@TA@ALN MNPs accelerate the synthesis of cartilage-specific proteins, and suppress catabolic-related genes expression and reactive oxygen species generation, affording additional protection to TMJ cartilage. In TMJOA mouse models, articular injection of γ-Fe2O3@TA@ALN MNPs effectively alleviates cartilage degeneration and subchondral bone loss in short and long terms, offering promising avenues for the development of therapeutic interventions for TMJOA.

Microgel-Crosslinked Thermo-Responsive Hydrogel Actuators with High Mechanical Properties and Rapid Response.

Smart hydrogels responsive to external stimuli are promising for various applications such as soft robotics and smart devices. High mechanical strength and fast response rate are particularly important for the construction of hydrogel actuators. Herein, tough hydrogels with rapid response rates are synthesized using vinyl-functionalized poly(N-isopropylacrylamide) (PNIPAM) microgels as macro-crosslinkers and N-isopropylacrylamide as monomers. The compression strength of the obtained PNIPAM hydrogels is up to 7.13 MPa. The response rate of the microgel-crosslinked hydrogels is significantly enhanced compared with conventional chemically crosslinked PNIPAM hydrogels. The mechanical strength and response rate of hydrogels can be adjusted by varying the proportion of monomers and crosslinkers. The lower critical solution temperature (LCST) of the PNIPAM hydrogels could be tuned by copolymerizing with ionic monomer sodium methacrylate. Thermo-responsive bilayer hydrogels are fabricated using PINPAM hydrogels with different LCSTs via a layer-by-layer method. The thermo-responsive fast swelling and shrinking properties of the two layers endow the bilayer hydrogel with anisotropic structures and asymmetric response characteristics, allowing the hydrogel to respond rapidly. The bilayer hydrogels are fabricated into clamps to grab small objects and flowers that mimicked the closure of petals, and it shows great application prospects in the field of actuators.

Construction of Zwitterionic Coatings with Lubricating and Antiadhesive Properties for Invisible Aligner Applications.

Invisible aligners have been widely used in orthodontic treatment but still present issues with plaque formation and oral mucosa abrasion, which can lead to complicated oral diseases. To address these issues, hydrophilic poly(sulfobetaine methacrylate) (polySBMA) coatings with lubricating, antifouling, and antiadhesive properties have been developed on the aligner materials (i.e., polyethylene terephthalate glycol, PETG) via a simple and feasible glycidyl methacrylate (GMA)-assisted coating strategy. Poly(GMA-co-SBMA) is grafted onto the aminated PETG surface via the ring-opening reaction of GMA (i.e., "grafting to" approach to obtain G-co-S coating), or a polySBMA layer is formed on the GMA-grafted PETG surface via free radical polymerization (i.e., "grafting from" approach to obtain G-g-S coating). The G-co-S and G-g-S coatings significantly reduce the friction coefficient of PETG surface. Protein adsorption, bacterial adhesion, and biofilm formation on the G-co-S- and G-g-S-coated surfaces are significantly inhibited. The performance of the coatings remains stable after storage in air or artificial saliva for 2 weeks. Both coatings demonstrate good biocompatibility in vitro and is not caused irritation to the oral mucosa of rats in vivo over 2 weeks. This study proposes a promising strategy for the development of invisible aligners with improved performance, which is beneficial for oral health treatment.

Microneedles loaded with cerium-manganese oxide nanoparticles for targeting macrophages in the treatment of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent inflammatory autoimmune disease characterised by persistent inflammation and joint damage with elevated levels of reactive oxygen species (ROS). Current treatment modalities for RA have significant limitations, including poor bioavailability, severe side effects, and inadequate targeting of inflamed joints. Herein, we synthesised cerium/manganese oxide nanoparticles (NPs) as efficient drug carriers with antioxidant and catalytic-like functions that can eliminate ROS to facilitate the polarization of macrophages phenotype from M1 to M2 and alleviate inflammation. Methotrexate (MTX), a first-line RA medication, was loaded into the NPs, which were further modified with bovine serum albumin (BSA) and integrated into dissolving hyaluronic acid-based microneedles (MNs) for transdermal delivery. RESULT: This innovative approach significantly enhanced drug delivery efficiency, reduced RA inflammation, and successfully modulated macrophage polarization toward an anti-inflammatory phenotype. CONCLUSION: This research not only presents a promising drug delivery strategy for RA but also contributes broadly to the field of immune disease treatment by offering an advanced approach for macrophage phenotypic reprogramming.

Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy.

The utilization of extracellular vesicles (EV) in immunotherapy, aiming at suppressing peripheral immune cells responsible for inflammation, has demonstrated significant efficacy in treating various inflammatory diseases. However, the clinical application of EV has faced challenges due to their inadequate targeting ability. In addition, most of the circulating EV would be cleared by the liver, resulting in a short biological half-life after systemic administration. Inspired by the natural microvesicles (MV, as a subset of large size EV) are originated and shed from the plasma membrane, we developed the immunosuppressive MV-mimetic (MVM) from endotoxin tolerant dendritic cells (DC) by a straightforward and effective extrusion approach, in which DC surface proteins were inherited for providing the homing ability to the spleen, while αCD3 antibodies were conjugated to the MVM membranes for specific targeting of T cells. The engineered MVM carried a large number of bioactive cargos from the parental cells, which exhibited a remarkable ability to promote the induction of regulatory T cells (Treg) and polarization of anti-inflammatory M2 macrophages. Mechanistically, the elevated Treg level by MVM was mediated due to the upregulation of miR-155-3p. Furthermore, it was observed that systemic and local immunosuppression was induced by MVM in models of sepsis and rheumatoid arthritis through the improvement of Treg and M2 macrophages. These findings reveal a promising cell-free strategy for managing inflammatory responses to infections or tissue injury, thereby maintaining immune homeostasis.

An analysis of the prognostic role of reactive oxygen species-associated genes in breast cancer.

BACKGROUND: This study aimed to type breast cancer in relation to reactive oxygen species (ROS), clinical indicators, single nucleotide variant (SNV) mutations, functional differences, immune infiltration, and predictive responses to immunotherapy or chemotherapy, and constructing a prognostic model. METHODS: We used uniCox analysis, ConsensusClusterPlus, and the proportion of ambiguous clustering (PAC) to analyze The Cancer Genome Atlas (TCGA) data to determine optimal groupings and obtain differentially expressed ROS-related genes. Clinical indicators were then combined with the classification results and the Chi-square test was used to assess differences. We further examined SNV mutations, and functional differences using gene set enrichment analysis (GSEA) analysis, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, immune cell infiltration, and response to immunotherapy and chemotherapy. A prognostic model for breast cancer was constructed using these differentially expressed genes, immunotherapy or chemotherapy responses, and survival curves. RT-qPCR was used to detect the differences in the expression of LCE3D, CA1, PIRT and SMR3A in breast cancer cell lines and normal breast epithelial cell line. RESULTS: We identified two distinct tumor types with significant differences in ROS-related gene expression, clinical indicators, SNV mutations, functional pathways, and immune infiltration. The response to specific chemotherapy drugs and immunotherapy treatments also documented significant differences. The prognostic model constructed with 16 genes linked to survival could efficiently divide patients into high- and low-risk groups. The high-risk group showed a poorer prognosis, higher tumor purity, distinct immune microenvironment, and lower immunotherapy response. RT-qPCR results showed that LCE3D, CA1, PIRT and SMR3A are highly expressed in breast cancer. CONCLUSION: Our methodical examination presented an enhanced insight into the molecular and immunological heterogeneity of breast cancer. It can contribute to the understanding of prognosis and offer valuable insights for personalized treatment strategies. Further, the prognostic model can potentially serve as a powerful tool for risk stratification and therapeutic decision-making in clinical settings.

Ablation of KIF2C in Purkinje cells impairs metabotropic glutamate receptor trafficking and motor coordination in male mice.

Kinesin family member 2C (KIF2C)/mitotic centromere-associated kinesin (MCAK), is thought to be oncogenic as it is involved in tumour progression and metastasis. Moreover, it also plays a part in neurodegenerative conditions like Alzheimer's disease and psychiatric disorders such as suicidal schizophrenia. Our previous study conducted on mice demonstrated that KIF2C is widely distributed in various regions of the brain, and is localized in synaptic spines. Additionally, it regulates microtubule dynamic properties through its own microtubule depolymerization activity, thereby affecting AMPA receptor transport and cognitive behaviour in mice. In this study, we show that KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells results in abnormal gait, reduced balance ability and motor incoordination in male mice. These data suggest that KIF2C is essential for maintaining normal transport and synaptic function of mGlu1 and motor coordination in mice. KEY POINTS: KIF2C is localized in synaptic spines of hippocampus neurons, and regulates excitatory transmission, synaptic plasticity and cognitive behaviour. KIF2C is extensively expressed in the cerebellum, and we investigated its functions in development and synaptic transmission of cerebellar Purkinje cells. KIF2C deficiency in Purkinje cells alters the expression of metabotropic glutamate receptor 1 (mGlu1) and the AMPA receptor GluA2 subunit at Purkinje cell synapses, and changes excitatory synaptic transmission, but not inhibitory transmission. KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells affects motor coordination, but not social behaviour in male mice.

Activated Natural Killer Cells-Dependent Dendritic Cells Recruitment and Maturation by Responsive Nanogels for Targeting Pancreatic Cancer Immunotherapy.

Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as CC motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8+ T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.

Redox-Regulated Conformational Change of Disulfide-Rich Assembling Peptides.

Disulfide bond formation is a common mechanism for regulating conformational changes in proteins during oxidative folding. Despite extensive studies of the use of multiple disulfide bonds to constrain peptide conformation, few studies have explored their usage in developing self-assembling peptides. Herein, we report that a thiol-rich peptide could fold into an amphiphilic ß-hairpin conformation through the formation of two hetero-disulfide bonds upon oxidation, subsequently self-assembling into a mechanically rigid hydrogel. Breaking disulfide bonds under reductive condition, the hydrogel exhibited a transition from hydrogel to solution. Molecular simulation revealed that intermolecular interaction between two tryptophan residues was indispensable for hydrogelation. This work is the first case of the use of multiple disulfide bonds to control conformational change and self-assembly, and provides a cell-compatible hydrogel material for potential biomedical application.

Hypoxia-responsive nanogel as IL-12 carrier for anti-cancer therapy.

In the past two decades, protein drugs have evolved to become the most successful and important strategy in cancer therapy. However, systematical administration of protein drugs may cause serious side effects. In order to prepare a new promising hydrophilic drugs carrier, we constructed a PEGylated hyaluronic acid nanogel (NI-MAHA-PEG nanogel) with hypoxia and enzymatic responsiveness, which can selectively release hydrophilic drugs interleukin-12 (IL-12) on demand in a tumor microenvironment. We observed that release of IL-12 from nanogels by hypoxia-responsive stimulation, nanogels have anti-tumor effects on melanoma. Compared with physiological conditions, the IL-12 release rate has achieved remarkable growth under hypoxic conditions. Similarly, the drug release rate increased significantly with the addition of 500 U ml-1 hyaluronidase. We provide a novel strategy to allow efficient delivery, on-demand release, and enhanced access of proteins to hypoxic tumor regions. The rational design of this nanogels drug delivery system can further explore the use of various drugs to treat many cancers.

Oppositely Charged Ti3 C2 Tx MXene Membranes with 2D Nanofluidic Channels for Osmotic Energy Harvesting.

Membrane-based reverse electrodialysis (RED) is considered as the most promising technique to harvest osmotic energy. However, the traditional membranes are limited by high internal resistance and low efficiency, resulting in undesirable power densities. Herein, we report the combination of oppositely charged Ti3 C2 Tx MXene membranes (MXMs) with confined 2D nanofluidic channels as high-performance osmotic power generators. The negatively or positively charged 2D MXene nanochannels exhibit typical surface-charge-governed ion transport and show excellent cation or anion selectivity. By mixing the artificial sea water (0.5 m NaCl) and river water (0.01 m NaCl), we obtain a maximum power density of ca. 4.6 Wm-2 , higher than most of the state-of-the-art membrane-based osmotic power generators, and very close to the commercialization benchmark (5 Wm-2 ). Through connecting ten tandem MXM-RED stacks, the output voltage can reach up 1.66 V, which can directly power the electronic devices.

Antibiotics Separation with MXene Membranes Based on Regularly Stacked High-Aspect-Ratio Nanosheets.

The uncontrolled release of antibiotics and pharmaceuticals into the environment is a worldwide increasing problem. Thus, highly efficient treatment technologies for wastewater are urgently needed. In this work, seven kinds of typical antibiotics (including water and alcohol soluble ones) are successfully separated from the corresponding aqueous and ethanolic solutions using highly regular laminated membranes. Our membranes are assembled with 2-4 µm titanium carbide nanosheets. The solvent permeance through such titanium carbide membrane is one order of magnitude higher than that through most polymeric nanofiltration membranes with similar antibiotics rejection. This high flux is due to the regular two-dimensional (2D) structure resulting from the large aspect ratio of titanium carbide nanosheets. Moreover, the electrostatic interaction between the surface terminations and the antibiotics also affects the rejection and enhances the antifouling property. Such 2D titanium carbide membranes further broaden the application scope of laminated materials for separation and purification of high value added drugs in academia and industry.

Integrated analysis of competing endogenous RNA networks revealing five prognostic biomarkers associated with colorectal cancer.

Colorectal cancer (CRC) is a common malignant tumor with high morbidity and mortality around the world. The aim of this study was to determine the genes significantly associated with the overall survival (OS) of CRC patients and predict their function in the competing endogenous RNA (ceRNA) regulation networks. We constructed the lncRNA-miRNA-mRNA networks according to the differentially expressed RNAs from the The Cancer Genome Atlas data sets of 561 CRC patients. Twelve differentially expressed messenger RNAs from the ceRNA networks were selected through a univariate Cox proportional hazards regression. Then, these genes were analyzed by using multivariate Cox proportional hazards stepwise regression to construct a prognostic model in which five genes (tensin 1, clusterin, proteolipid protein 1, epiregulin, and transcription factor Spi-B) were included. The Kaplan-Meier risk survival analysis showed that this five-gene signature independently predicted a 5-year overall survival in CRC patients (P < 0.001). Furthermore, significance was verified according to two irrelevant Gene Expression Omnibus (GEO) data sets (GSE38832 and GSE39582). The verified five-gene model of CRC can be used to predict patient prognosis and will inform postoperational evaluation and follow-up strategies.

LONGITUDINAL CHANGES IN CHOROIDAL AND RETINAL THICKNESSES IN CHILDREN WITH MYOPIC SHIFT.

PURPOSE: To elucidate the development of the choroid and retina in children, and to explore changes in these during myopic shift. METHODS: A total of 118 children aged 7 to 12 years participated in this 1-year longitudinal study. Children underwent several examinations at baseline and follow-up, including cycloplegic refraction, axial length measurement, and swept-source optical coherence tomography. Thickness changes in the choroid and retina were compared among children with or without myopic shift. RESULTS: Eighty-eight children (74.6%) developed a myopic shift after 1 year, and their central foveal choroid was significantly attenuated (P < 0.01). No significant change was observed in choroids of children without myopic shift (P = 0.83). Choroidal thickness decreased in all subfields during myopic shift, whereas the thickness of the retinal layers increased or were unchanged in most subfields. Axial length increase and central foveal choroidal thinning were associated with myopic shift (R = 0.157, P < 0.01), but axial length increase was not significantly related to choroidal thinning (P > 0.05). CONCLUSION: Choroidal thinning occurs early in myopic progression. Axial length increase and choroidal thinning are independently associated with myopic shift.

PEGylated hollow gold nanoparticles for combined X-ray radiation and photothermal therapy in vitro and enhanced CT imaging in vivo.

Up until now, hollow gold nanoparticles (HGNPs) with a spherical cavity have garnered much interest as theranostic agents in cancer therapy due to their high X-ray absorption and photothermal conversion ability. Herein, we describe the design of PEGylated hollow gold nanoparticles (mPEG@HGNPs) for combined X-ray radiation and photothermal therapy in vitro and enhanced computed tomography (CT) imaging in vivo using a breast tumor model. In vitro results revealed that mPEG@HGNPs could achieve a synergistic antitumor effect when irradiated by combined X-ray radiation and 808 nm near infrared laser light. Furthermore, mPEG@HGNPs exhibited a favorable tumor targeting effect and good CT contrast enhancement in both xenografted and orthotopic breast tumor models, due to the stealth effect of PEG which increased the enhanced permeability and retention (EPR) effect. These results suggest that mPEG@HGNPs may serve as multifunctional nanocomposites for cancer combination therapy and, thus, should be further studied.

The performance of T-cell Xtend reagent in increasing blood storage times for interferon gamma release assays.

BACKGROUND: T-cell Xtend (TCX) was introduced to extend the blood storage time for T-SPOT.TB test, a widely used commercial interferon gamma release assay (IGRA) for rapid in vitro tuberculosis. METHODS: A total of 99 Uyghur suspected tuberculosis patients were recruited in this study. T-SPOT.TB test was performed with fresh blood (controls), 36 hours delayed blood and delayed and TCX-treated (at 36 hours) blood from each patient, respectively. RESULTS: White blood cells and lymphocytes proportion in peripheral blood mononuclear cells s and spot-forming cells in positive control wells decreased significantly in delayed blood samples when compared with controls, while this decrease was not detected in TCX-treated group. In the 58 patients with paired T-SPOT.TB results of three groups of samples, a higher positive rate was observed in TCX-treated group than both in controls and untreated group (41.4% vs 37.9% and 25.9%). The concordance of T-SPOT.TB results between the treated group and controls was 0.856, whereas the agreement between controls and untreated group was unsatisfactory (0.649). In the 23 elderly patients (>70 years old) with paired T-SPOT.TB results of controls and TCX group, treated group showed a non-significant trend toward higher positive rate than controls (43.5% vs 26.1%, P=.22). Meanwhile, TCX treatment reduced the risk of false negative T-SPOT.TB results in the elderly population. CONCLUSION: Deterioration of blood sample caused by long storage time can be neutralized by TCX treatment. The results provide data for the utility of TCX in a novel population and in Asian region, and reveal the potential of TCX to improve the accuracy of T-SPOT.TB test in elderly population.

Comparison of Refractive Measures of Three Autorefractors in Children and Adolescents.

SIGNIFICANCE: Our study found a good agreement between three autorefractors. Not only will readers benefit as they can now compare data measured with either device in different studies but the three devices can be used in the same study to generate one pool of data, which can be analyzed together. PURPOSE: The present study aims to evaluate the agreement of three commonly used autorefractors in children and adolescents, and the potential for their interchangeable application in a large-scale study. METHODS: Participants from seven schools were enrolled using cluster sampling. Refractive errors were measured using the following three autorefractors under cycloplegic conditions in random sequence: Topcon KR-8900, Nidek ARK-510A, and Huvitz HRK-7000A. Refractive errors were compared in terms of spherical equivalent refraction (SER), cylinder power, and the J0 and J45 by repeated-measures analysis of variance (RM-ANOVA) and Bland-Altman 95% limits of agreement (95% LoA). RESULTS: A total of 2072 participants aged from 4 to 18 years were included. The mean ± SD and 95% LoA of the differences in SER between Topcon and Nidek, Topcon and Huvitz, and Nidek and Huvitz were 0.01 ± 0.24D (-0.46 to 0.48), -0.06 ± 0.31D (-0.66 to 0.54), and -0.07 ± 0.26D (-0.58 to 0.44), and those for the differences in cylinder power were -0.07 ± 0.26D (-0.57 to 0.44), 0.01 ± 0.32D (-0.63 to 0.64), and 0.07 ± 0.28D (-0.48 to 0.62), respectively (RM-ANOVA, P < .001). Further, the mean differences in J0 and J45 between each refractor pair ranged from -0.03 to 0.01, and the 95% LoA were -0.78 to 0.74, -0.79 to 0.74, and -0.73 to 0.72 for J0 and -0.86 to 0.87, -0.86 to 0.88, and -0.83 to 0.84 for J45, respectively. CONCLUSIONS: Our study will allow for use of these three autorefractors interchangeably in large screening studies.

Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.

One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.