The specific sizes that determine optimal nanoparticle tumor accumulation, penetration, and treatment remain inconclusive because many studies compared nanoparticles with multiple physicochemical ...variables (e.g., chemical structures, shapes, and other physical properties) in addition to the size. In this study, we synthesized amphiphilic block copolymers of 7-ethyl-10-hydroxylcamptothecin (SN38) prodrug and fabricated micelles with sizes ranging from 20 to 300 nm from a single copolymer. The as-prepared micelles had exactly the same chemical structures and similar physical properties except for size, which provided an ideal platform for a systematic investigation of the size effects in cancer drug delivery. We found that the micelle’s blood circulation time and tumor accumulation increased with the increase in their diameters, with optimal diameter range of 100 to 160 nm. However, the much higher tumor accumulation of the large micelles (100 nm) did not result in significantly improved therapeutic efficacy, because the large micelles had poorer tumor penetration than the small ones (30 nm). An optimal size that balances drug accumulation and penetration in tumors is critical for improving the therapeutic efficacy of nanoparticulate drugs.
Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD‐L1 that exhausts antigen‐specific CD8+ T cells through PD‐1 ...receptors. Checkpoint blockade antibodies against PD‐1 or PD‐L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD‐1 receptors on their membranes, which enhance antitumor responses by disrupting the PD‐1/PD‐L1 immune inhibitory axis, are reported. PD‐1 NVs exhibit a long circulation and can bind to the PD‐L1 on melanoma cancer cells. Furthermore, 1‐methyl‐tryptophan, an inhibitor of indoleamine 2,3‐dioxygenase can be loaded into the PD‐1 NVs to synergistically disrupt another immune tolerance pathway in the tumor microenvironment. Additionally, PD‐1 NVs remarkably increase the density of CD8+ tumor infiltrating lymphocytes in the tumor margin, which directly drive tumor regression.
Cellular nanovesicles (NVs) presenting PD‐1 receptors on their membrane are genetically engineered for disturbing the PD1/PD‐L1 immune inhibitory axis. Additionally, 1‐methyl‐tryptophan (1‐MT), an inhibitor of indoleamine 2,3‐dioxygenase (IDO) can be loaded into the PD‐1 NVs to synergistically promote antitumor efficacy. This formulation provides a promising strategy that leverages functions of immune checkpoint blockade and encapsulated therapeutics for enhancing cancer immunotherapy.
Reactive oxygen species (ROS) plays a key role in therapeutic effects as well as side effects of platinum drugs. Cisplatin mediates activation of nicotinamide adenine dinucleotide phosphate (NADPH) ...oxidase (NOX), which triggers oxygen (O2) to superoxide radical (O2 • –) and its downstream H2O2. Through the Fenton’s reaction, H2O2 could be catalyzed by Fe2+/Fe3+ to the toxic hydroxyl radicals (•OH), which cause oxidative damages to lipids, proteins, and DNA. By taking the full advantage of Fenton’s chemistry, we herein demonstrated tumor site-specific conversion of ROS generation induced by released cisplatin and Fe2+/Fe3+ from iron-oxide nanocarriers with cisplatin(IV) prodrugs for enhanced anticancer activity but minimized systemic toxicity.
The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin‐producing β‐cells by islet‐specific autoreactive T cells. Inhibition of islet‐specific autoreactive T cells to rescue ...β‐cells is a promising approach to treat new‐onset T1D. The immune checkpoint signal axis programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD‐L1 to produce immunosuppressive platelets. The PD‐L1‐overexpressing platelets (designated PD‐L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non‐obese diabetic (NOD) mice, protecting the insulin‐producing β‐cells from destruction. Moreover, PD‐L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β‐cells by PD‐L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.
Platelets are genetically engineered to overexpress programmed death‐ligand 1 (PD‐L1) to maintain immune tolerance in the pancreas and reverse new‐onset Type 1 diabetes in non‐obese diabetic (NOD) mice. The PD‐L1‐expressing platelets may suppress the activity of pancreas autoreactive T cells and increase the percentage of the regulatory T cells in newly hyperglycemic NOD mice, protecting the insulin‐producing β‐cells from destruction.
To improve the recognition rate of lower limb actions based on surface electromyography (sEMG), an effective weighted feature method is proposed, and an improved genetic algorithm support vector ...machine (IGA-SVM) is designed in this paper. First, for the problem of high feature redundancy and low discrimination in the surface electromyography feature extraction process, the weighted feature method is proposed based on the correlation between muscles and actions. Second, to solve the problem of the genetic algorithm selection operator easily falling into a local optimum solution, the improved genetic algorithm-support vector machine is designed by championship with sorting method. Finally, the proposed method is used to recognize six types of lower limb actions designed, and the average recognition rate reaches 94.75%. Experimental results indicate that the proposed method has definite potentiality in lower limb action recognition.
Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with ...diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'.
Reduced β-cell function and insulin deficiency are hallmarks of diabetes mellitus, which is often accompanied by the malfunction of glucagon-secreting α-cells. While insulin therapy has been ...developed to treat insulin deficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains inadequate. Here, we describe a transdermal patch that mimics the inherent counterregulatory effects of β-cells and α-cells for blood glucose management by dynamically releasing insulin or glucagon. The two modules share a copolymerized matrix but comprise different ratios of the key monomers to be “dually responsive” to both hyper- and hypoglycemic conditions. In a type 1 diabetic mouse model, the hybrid patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy with simulated delayed meal or insulin overdose.
Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell ...function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm
). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.
The motor imagery brain-computer interface (MI-BCI) based on electroencephalography (EEG) is a widely used human-machine interface paradigm. However, due to the non-stationarity and individual ...differences among subjects in EEG signals, the decoding accuracy is limited, affecting the application of the MI-BCI. In this paper, we propose the EISATC-Fusion model for MI EEG decoding, consisting of inception block, multi-head self-attention (MSA), temporal convolutional network (TCN), and layer fusion. Specifically, we design a DS Inception block to extract multi-scale frequency band information. And design a new cnnCosMSA module based on CNN and cos attention to solve the attention collapse and improve the interpretability of the model. The TCN module is improved by the depthwise separable convolution to reduces the parameters of the model. The layer fusion consists of feature fusion and decision fusion, fully utilizing the features output by the model and enhances the robustness of the model. We improve the two-stage training strategy for model training. Early stopping is used to prevent model overfitting, and the accuracy and loss of the validation set are used as indicators for early stopping. The proposed model achieves within-subject classification accuracies of 84.57% and 87.58% on BCI Competition IV Datasets 2a and 2b, respectively. And the model achieves cross-subject classification accuracies of 67.42% and 71.23% (by transfer learning) when training the model with two sessions and one session of Dataset 2a, respectively. The interpretability of the model is demonstrated through weight visualization method.
This paper investigates the problem of path following control of the underactuated autonomous underwater vehicles in the presence of model uncertainties and external disturbances. With the ...three-dimensional path following error model established based on virtual guidance method, a path following robust control system is proposed using the command filtered backstepping control, neural networks, and adaptive control techniques. Then, a Lyapunov-based stability analysis demonstrates that all the signals are bounded and path following errors ultimately converge to a neighborhood of the origin. Following advantages are highlighted in this paper: 1) the derivative of virtual control is obtained via a second-order filter, which avoids explosion of complexity in the traditional backstepping design, and filters out high frequency measurement noise to keep the control system more robust, and a filtered error compensation loop is developed to guarantee the approximation precision between the virtual control signals and the filtered signals and 2) the presented controller is easily put into practice without any former knowledge of vehicle parameters and external environmental disturbances. Finally, the simulations are conducted, and results illustrate the effectiveness and good robustness of the proposed control system through a new class of flying wing autonomous underwater vehicle.
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