Cell membrane coating nanotechnology, which endows nanoparticles with unique properties, displays excellent translational potential in cancer diagnosis and therapy. However, the preparation and ...evaluation of these cell membrane‐coated nanoparticles are based on cell lines and cell‐line‐based xenograft mouse models. The feasibility of cell membrane‐camouflaged nanomaterials is tested in a preclinical setting. Head and neck squamous cell carcinoma (HNSCC) patient‐derived tumor cell (PDTC) membranes are coated onto gelatin nanoparticles (GNPs) and the resulting PDTC@GNPs show efficient targeting to homotypic tumor cells and tissues in patient‐derived xenograft (PDX) models. When the donor‐derived cell membrane of PDTC@GNPs matched those of the host cells, significant targeting capability is observed. In contrast, mismatch between the donor and host results in weak targeting. Furthermore, it is demonstrated that autologous separation and administration of cellular membranes and anticancer cisplatin (Pt)‐loaded PDTC@GNPs, respectively, lead to almost complete tumor ablation in a subcutaneous model and effectively inhibit tumor recurrence in a postsurgery model. The work presented here reinforces the translation of these biomimetic nanoparticles for clinical applications and offers a simple, safe, and effective strategy for personalized cancer treatment.
Cancer cell membrane‐coated nanoparticles, which inherit homologous cancer targeting capability from the source cells, are used for personalized cancer treatment in patient‐derived xenograft models. This represents a simple, safe, and effective strategy for personalized cancer treatment.
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha ...(SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
An artificial neural network (ANN) optimized by genetic algorithm (GA) is an established prediction model of bending force in hot strip rolling. The data are collected from factory of steel ...manufacture. Entrance temperature and thickness, exit thickness, strip width, rolling force, rolling speed, roll shifting, target profile, and yield strength of strip are selected to be independent variables as network inputs. MATLAB software is utilized for establishing GA-ANN model and achieving the purpose of obtaining the bending force as results of setup model, as well as the GA method is used to optimize the initial weights and biases of the backpropagation neural network. Mean absolute error (MAE), mean absolute percentage error (MAPE), root mean squared error (RMSE), and correlation coefficient are adapted to evaluate the performance of the model. The predictive results are compared with the measured results to verify the accuracy of the GA-ANN prediction model. It is found that the optimization effect is the best with the population size 40 crossover probability of 0.7 and the mutation probability of 0.05 at the same time, the fitness function value can reach 80.7. In addition, the ANN architecture 9-11-1 trained with Bayesian regulation “trainbr” function has the best performance with mean absolute error of 0.01 and correlation coefficient of 0.983. With a deeper understanding of neural networks through the analysis of the GA-ANN model, the proposed model can be flexibly used for on-line controlling and rolling schedule optimizing.
Biomimetic cell‐membrane‐camouflaged nanoparticles with desirable features have been widely used for various biomedical applications. However, the current research focuses on single cell membrane ...coating and using multiple cell membranes for nanoparticle functionalization is still challenging. In this work, platelet (PLT) and leukocyte (WBC) membranes are fused, PLT–WBC hybrid membranes are coated onto magnetic beads, and then their surface is modified with specific antibodies. The resulting PLT–WBC hybrid membrane‐coated immunomagnetic beads (HM‐IMBs) inherit enhanced cancer cell binding ability from PLTs and reduce homologous WBC interaction from WBCs, and are further used for highly efficient and highly specific isolation of circulating tumor cells (CTCs). By using spiked blood samples, it is found that, compared with commercial IMBs, the cell separation efficiency of HM‐IMBs is improved to 91.77% from 66.68% and the cell purity is improved to 96.98% from 66.53%. Furthermore, by using the HM‐IMBs, highly pure CTCs are successfully identified in 19 out of 20 clinical blood samples collected from breast cancer patients. Finally, the robustness of HM‐IMBs is verified in downstream CTC analysis such as the detection of PIK3CA gene mutations. It is anticipated that this novel hybrid membrane coating strategy will open new possibilities for overcoming the limitations of current theranostic platforms.
Biomimetic platelet–leukocyte hybrid membrane‐coated immunomagnetic beads with enhanced cancer binding and reduced leukocyte interaction are used for ultrahigh‐efficiency and ‐purity isolation of circulating tumor cells from the blood samples of cancer patient. The combination of biomimetic hybrid cell membrane coating and immunomagnetic beads embodies a novel materials design strategy and presents a compelling class of advanced functional materials.
For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have ...reported a phenomenon known as “accelerated blood clearance (ABC)” where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane‐coated Fe3O4 nanoparticles (Fe3O4@RBC NPs) rely on CD47, which is a “don't eat me” marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein‐alpha (SIRP‐α) receptor. Fe3O4@RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe3O4@RBC NPs does not elicit immune responses on neither the cellular level (myeloid‐derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane‐camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long‐existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.
Red blood cell membrane‐camouflaged Fe3O4 nanoparticles (Fe3O4@RBC NPs) exhibit prolonged circulation time in the blood with no adverse effects. There is little change between a first and second dose, and no accelerated blood clearance is seen, as is generally the case for PEGylated nanomaterials. This is a significant advancement toward developing biomaterials that are able to resist both immune response and rapid clearance.
Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect ...in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signaling was activated in a Tgfbr1/Pten‐knockout HNSCC mouse model. Notch signaling inhibition using a γ‐secretase inhibitor (GSI‐IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment. In addition, flow cytometry analysis indicated that Notch signaling inhibition reduced the sub‐population of myeloid‐derived suppressor cells (MDSCs), tumour‐associated macrophages (TAMs) and regulatory T cells (Tregs), as well as immune checkpoint molecules (PD1, CTLA4, TIM3 and LAG3), in the circulation and in the tumour. Immunohistochemistry (IHC) of human HNSCC tissues demonstrated that elevation of the Notch1 downstream target HES1 was correlated with MDSC, TAM and Treg markers and with immune checkpoint molecules. These results suggest that modulating the Notch signaling pathway may decrease MDSCs, TAMs, Tregs and immune checkpoint molecules in HNSCC.
What's new?
Tumor survival depends on sneaking past the body's own immune defenses. Here, the authors probed how cancer cells exploit the Notch signaling pathway to evade immune destruction. Looking at HNSCC cells, they first showed that Notch1 signaling is activated in the tumor cells. Then, they showed that inhibiting the Notch signaling pathway decreased the tumor burden, as well as markedly reducing the production of immunosuppressive cells, such as tumor associated macrophages and immunosuppressive regulatory T cells. Thus, treatments targeting Notch1 could be useful against HNSCC.
Although anti-PD-1 immunotherapy is widely used to treat melanoma, its efficacy still has to be improved. In this work, we present a therapeutic method that combines immunotherapy and starvation ...therapy to achieve better antitumor efficacy. We designed the CMSN-GOx method, in which mesoporous silica nanoparticles (MSN) are loaded with glucose oxidase (GOx) and then encapsulate the surfaces of cancer cell membranes to realize starvation therapy. By functionalizing the MSN’s biomimetic surfaces, we can synthesize nanoparticles that can escape the host immune system and homologous target. These attributes enable the nanoparticles to have improved cancer targeting ability and enrichment in tumor tissues. Our synthetic CMSN-GOx complex can ablate tumors and induce dendritic cell maturity to stimulate an antitumor immune response. We performed an in vivo analysis of these nanoparticles and determined that our combined therapy CMSN-GOx plus PD-1 exhibits a better antitumor therapeutic effect than therapies using CMSN-GOx or PD-1 alone. Additionally, we used the positron emission tomography imaging to measuring the level of glucose metabolism in tumor tissues, for which we investigate the effect with the cancer therapy in vivo.
We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in ...modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6-min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes.
The adenosine‐induced immunosuppression hampers the immune response toward tumor cells and facilitates the tumor cells to evade immunosurveillance. CD73, an ecto‐5‐nucleotidase, is the ectoenzyme ...dephosphorylating extracellular AMP to adenosine. Here, using immunocompetent transgenic head and neck squamous cell carcinoma (HNSCC) mouse model, immune profiling showed high expression of CD73 on CD4+ and CD8+ T cells was associated with an “exhausted” phenotype. Further, treatment with anti‐CD73 monoclonal antibody (mAb) significantly blunted the tumor growth in the mouse model, and the blockade of CD73 reversed the “exhausted” phenotype of CD4+ and CD8+ T cells through downregulation of total expression of PD‐1 and CTLA‐4 on T cells. Whereas the population of CD4+CD73hi/CD8+CD73hi T cells expressed higher CTLA‐4 and PD‐1 as compared to untreated controls. In addition, the human tissue microarrays showed the expression of CD73 is upregulated on tumor infiltrating immune cells in patients with primary HNSCC. Moreover, CD73 expression is an independent prognostic factor for poor outcome in our cohort of HNSCC patients. Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC.
What's new?
Tumor cells employ various immunosuppressive mediators to evade immune detection and thereby escape mechanisms for tumor elimination. While cancer immunotherapeutic agents have been developed to counter this, some patients fail to respond, necessitating the development of alternative immunosuppressive approaches. Here, immune profiling in a head and neck squamous cell carcinoma (HNSCC) mouse model revealed high expression of the ecto‐5‐nucleotidase CD73 on CD4+ and CD8+ T cells. Treatment with an anti‐CD73 antibody suppressed tumor growth and restored T‐cell effector function. CD73 expression was further found to be upregulated in human HNSCC tissues, where it was prognostic for poor outcome.
•A series of UHPC-GFRP hybrid columns were tested under constant axial loading and cyclic lateral displacements.•The seismic responses of specimens were evaluated from various aspects, including ...failure modes, hysteretic responses, and strain profiles.•Influences of lateral loading directions, concrete types, reinforcement types, and longitudinal reinforcement ratios were discussed.
The combination of ultra-high performance concrete (UHPC) and glass fiber reinforced polymer (GFRP) bars offers a promising and viable design option for future infrastructure in the extremely harsh environment. However, studies carried out on this kind of structure are rather limited, especially for its seismic behavior under non-principal bending. This paper presents an experimental program on eight columns (four UHPC-GFRP hybrid columns, three UHPC columns and one reinforced concrete column) tested under lateral displacements with loading angles of 0° and 45°. Other changes of interest include types of concrete, types of reinforcement, and longitudinal reinforcement ratios. The seismic responses of specimens were discussed and analyzed in detail from various aspects, including cracking patterns, failure modes, hysteretic responses, and strain profiles. The experiment results reveal that the introduction of GFRP bars is effective in restricting the development of cracks while having limited negative influence on the seismic performance of UHPC columns, demonstrating the practicability of the UHPC-GFRP hybrid column. Furthermore, in contrast to reinforced concrete columns, it has been observed that UHPC specimens exhibit a low sensitivity to the direction of lateral loading with regard to cracking patterns and energy dissipation capacity.
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