Oral exosome-like nanovesicles from Phellinus linteus suppress metastatic hepatocellular carcinoma by reactive oxygen species generation and microbiota rebalancing.

The biomedical application of nanotechnology in cancer treatment has demonstrated significant potential for improving treatment efficiencies and ameliorating adverse effects. However, the medical translation of nanotechnology-based nanomedicines faces challenges including hazardous environmental effects, difficulties in large-scale production, and possible excessive costs. In the present study, we extracted and purified natural exosome-like nanoparticles (ELNs) from Phellinus linteus. These nanoparticles (denoted as P-ELNs) had an average particle size of 154.1 nm, displayed a negative zeta potential of -31.3 mV, and maintained stability in the gastrointestinal tract. Furthermore, P-ELNs were found to contain a diverse array of functional components, including lipids and pharmacologically active small-molecule constituents. In vitro investigations suggested that they exhibited high internalization efficiency in liver tumor cells (Hepa 1-6) and exerted significant anti-proliferative, anti-migratory, and anti-invasive effects against Hepa 1-6 cells. Strikingly, the therapeutic outcomes of oral P-ELNs were confirmed in an animal model of metastatic hepatocellular carcinoma by amplifying reactive oxygen species (ROS) and rebalancing the gut microbiome. These findings demonstrate the potential of P-ELNs as a promising oral therapeutic platform for liver cancer treatment.

Glucose-responsive insulin microneedle patches for long-acting delivery and release visualization.

Limited drug loading and incomplete drug release are two major obstacles that traditional polymeric microneedles (MNs) have to overcome. For smart controlled-release MNs, since drug release duration is uncertain, a clear indication of the finish of drug release is also important for patient guidance on the timing of the next dose. In this study, MN with a triple structure of a glucose-responsive shell, loaded insulin powders and a colored propelling inner core (inspired by the mechanism of osmotic pump) was innovatively constructed. The MN patch could release insulin according to blood glucose levels (BGLs) and had excellent drug loading, more complete drug release, and good drug stability, which significantly prolonged the normoglycemic time. An approximately 0.3 cm2 patch has a hypoglycemic effect on diabetic mice for up to 24 h. Moreover, the fading of the inner core could indicate the release process of the loaded drug and can help to facilitate uninterrupted closed loop therapy for patients. The designed triple MN structure is also suitable, and can be used in the design of other smart MN drug delivery systems to further improve their drug loading capacity and simultaneously achieve more complete, smart controlled and visualized drug release.

Natural lipid nanoparticles extracted from Morus nigra L. leaves for targeted treatment of hepatocellular carcinoma via the oral route.

The clinical application of conventional medications for hepatocellular carcinoma treatment has been severely restricted by their adverse effects and unsatisfactory therapeutic effectiveness. Inspired by the concept of 'medicine food homology', we extracted and purified natural exosome-like lipid nanoparticles (LNPs) from black mulberry (Morus nigra L.) leaves. The obtained MLNPs possessed a desirable hydrodynamic particle size (162.1 nm), a uniform size distribution (polydispersity index = 0.025), and a negative surface charge (-26.6 mv). These natural LNPs were rich in glycolipids, functional proteins, and active small molecules (e.g., rutin and quercetin 3-O-glucoside). In vitro experiments revealed that MLNPs were preferentially internalized by liver tumor cell lines via galactose receptor-mediated endocytosis, increased intracellular oxidative stress, and triggered mitochondrial damage, resulting in suppressing the viability, migration, and invasion of these cells. Importantly, in vivo investigations suggested that oral MLNPs entered into the circulatory system mainly through the jejunum and colon, and they exhibited negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation. These findings collectively demonstrate the potential of MLNPs as a natural, safe, and robust nanomedicine for oral treatment of hepatocellular carcinoma.

Micro SleepNet: efficient deep learning model for mobile terminal real-time sleep staging.

The real-time sleep staging algorithm that can perform inference on mobile devices without burden is a prerequisite for closed-loop sleep modulation. However, current deep learning sleep staging models have poor real-time efficiency and redundant parameters. We propose a lightweight and high-performance sleep staging model named Micro SleepNet, which takes a 30-s electroencephalography (EEG) epoch as input, without relying on contextual signals. The model features a one-dimensional group convolution with a kernel size of 1 × 3 and an Efficient Channel and Spatial Attention (ECSA) module for feature extraction and adaptive recalibration. Moreover, the model efficiently performs feature fusion using dilated convolution module and replaces the conventional fully connected layer with Global Average Pooling (GAP). These design choices significantly reduce the total number of model parameters to 48,226, with only approximately 48.95 Million Floating-point Operations per Second (MFLOPs) computation. The proposed model is conducted subject-independent cross-validation on three publicly available datasets, achieving an overall accuracy of up to 83.3%, and the Cohen Kappa is 0.77. Additionally, we introduce Class Activation Mapping (CAM) to visualize the model's attention to EEG waveforms, which demonstrate the model's ability to accurately capture feature waveforms of EEG at different sleep stages. This provides a strong interpretability foundation for practical applications. Furthermore, the Micro SleepNet model occupies approximately 100 KB of memory on the Android smartphone and takes only 2.8 ms to infer one EEG epoch, meeting the real-time requirements of sleep staging tasks on mobile devices. Consequently, our proposed model has the potential to serve as a foundation for accurate closed-loop sleep modulation.

A Novel Thermal Tactile Sensor Based on Micro Thermoelectric Generator for Underwater Flow Direction Perception.

Underwater vehicles can operate independently in the exploitation of marine resources. However, water flow disturbance is one of the challenges underwater vehicles must face. The underwater flow direction sensing method is a feasible way to overcome the challenges but faces difficulties such as integrating the existing sensors with underwater vehicles and high-cost maintenance fees. In this research, an underwater flow direction sensing method based on the thermal tactility of the micro thermoelectric generator (MTEG) is proposed, with the theoretical model established. To verify the model, a flow direction sensing prototype is fabricated to carry out experiments under three typical working conditions. The three typical flow direction conditions are: condition No. 1, in which the flow direction is parallel to the x-axis; condition No. 2, in which the flow direction is at an angle of 45° to the x-axis; and condition No. 3, which is a variable flow direction condition based on condition No. 1 and condition No. 2. According to the experimental data, the variations and orders of the prototype output voltages under three conditions fit the theoretical model, which means the prototype can identify the flow direction of three conditions. Besides, experimental data show that in the flow velocity range of 0~5 m/s and the flow direction variation range of 0~90°, the prototype can accurately identify the flow direction in 0~2 s. The first time utilizing MTEG on underwater flow direction perception, the underwater flow direction sensing method proposed in this research is cheaper and easier to be applied on the underwater vehicles than traditional underwater flow direction sensing methods, which means it has great application prospects in underwater vehicles. Besides, the MTEG can utilize the waste heat of the underwater vehicle battery as the energy source to achieve self-powered work, which greatly enhances its practical value.

Approaches and materials for endocytosis-independent intracellular delivery of proteins.

The intracellular delivery of proteins is of great significance. For diseases such as cancer, heart disease and neurodegenerative diseases, many important pharmacological targets are located inside cells. For genetic engineering and cell engineering, various functional proteins need to be delivered into cells for gene editing or cell state regulation. However, most existing protein delivery strategies involve endosomal escape (endocytosis-dependent), resulting in inefficient delivery due to endosome trapping. In contrast, endocytosis-independent intracellular delivery, which refers to the directly delivery of proteins across the cell membrane to the cytoplasm, will bypass the low efficiency of early endosomal escape, avoid protein inactivation caused by late endosome/lysosome, fundamentally improve the intracellular delivery efficiency, and open up a new way for intracellular protein delivery. In this review, the latest advances in direct intracellular delivery of proteins through membrane perforation, membrane translocation, and membrane fusion were summarized. The mechanisms, related materials and potential therapeutic in living cells/in vivo for each approach were discussed in detail, and the future development in this promising field was briefly presented.

Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation.

Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer, their inefficient therapeutic outcomes, serious adverse effects, and high cost of mass production remain crucial challenges. Herein, we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers (TFENs). These nanovehicles had desirable particle sizes (131 nm), exosome-like morphology, and negative zeta potentials. Furthermore, TFENs were found to contain large amounts of polyphenols, flavonoids, functional proteins, and lipids. Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species (ROS) amplification. The increased intracellular ROS amounts could not only trigger mitochondrial damage, but also arrest cell cycle, resulting in the in vitro anti-proliferation, anti-migration, and anti-invasion activities against breast cancer cells. Further mice investigations demonstrated that TFENs after intravenous (i.v.) injection or oral administration could accumulate in breast tumors and lung metastatic sites, inhibit the growth and metastasis of breast cancer, and modulate gut microbiota. This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v. and oral routes.

Edible plant-derived nanotherapeutics and nanocarriers: recent progress and future directions.

INTRODUCTION: High drug delivery efficiency, desirable therapeutic effects, and low toxicity have become crucial to develop nanotherapeutics. Natural nanoparticles (NPs) from edible plants contain a large quantity of bioactive small molecules, proteins, glycolipids, and microRNAs. The development of these NPs has rapidly attracted increasing attention due to their merits of green production, excellent biocompatibility, anti-inflammatory activities, and antitumor capacities. AREAS COVERED: Here, we introduce the extraction, purification, and construction strategies of plant-derived exosome-like NPs (PDENs) and expound on their physicochemical properties, biomedical functions, and therapeutic effects against various diseases. We also recapitulate future directions and challenges of the emerging nanotherapeutics. EXPERT OPINION: PDENs have been used as natural nanotherapeutics and nanocarriers. The challenges of applying PDENs primarily stem from the lack of understanding of the mechanisms that drive the tissue-specific targeting properties. Elucidating the underlying targeting mechanisms is one of the major focuses in this review, which helps to gain new research opportunities for the development of natural nanotherapeutics. Despite excellent biosafety and therapeutic effects in the treatment of various diseases, the medical translation of these NPs has still been limited by low yields and cold-chain dependence. Therefore, exploiting new techniques will be required for their massive production and storage.

Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy.

Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin (DOX)-loaded silk fibroin-based nanoparticles (NPs) with surface functionalization by photosensitizer (N770). The obtained nanotheranostics (N770-DOX@NPs) had desirable particle size (157 nm) and negative surface charge (-25 mV). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli (acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared (NIR) fluorescence imaging, photothermal imaging, and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumor retardation effect among all treatment groups based on tumor-bearing mouse models and a patient-derived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imaging-guided mitochondrial phototherapy (photothermal therapy and photodynamic therapy) and chemotherapy. Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.

'Green' nanotherapeutics from tea leaves for orally targeted prevention and alleviation of colon diseases.

Although synthesized nanotherapeutics (NTs) are attractive for the oral treatment of colon diseases, their clinical translations are constrained by the unsatisfactory therapeutic outcomes, potential adverse effects, and high cost of mass production. Here, we report the development of tea leaf-derived natural NTs with desirable particle sizes (140.0 nm) and negative surface charge (-14.6 mV). These natural exosome-like NTs were found to contain large amounts of lipids, some functional proteins, and many bioactive small molecules. Specifically, galactose groups on the surface of NTs could mediate their specific internalization by macrophages via galactose receptor-mediated endocytosis. Moreover, these NTs were able to reduce the production of reactive oxygen species, inhibit the expression of pro-inflammatory cytokines, and increase the amount of anti-inflammatory IL-10 secreted by macrophages. Orally administered NTs could efficiently inhibit the inflammatory bowel responses, restore disrupted colonic barriers and enhance the diversity and overall abundance of gut microbiota, thereby preventing or alleviating inflammatory bowel disease and colitis-associated colon cancer. The present study brings new insights to the facile application of a versatile and robust natural nanoplatform for the prevention and treatment of colon diseases.

Oral nanotherapeutics with enhanced mucus penetration and ROS-responsive drug release capacities for delivery of curcumin to colitis tissues.

The therapeutic efficacies of oral nanotherapeutics for ulcerative colitis (UC) are seriously hindered by the lack of mucus-penetrating capacity and uncontrolled drug release. To overcome these limitations, the surface of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) was functionalized with pluronic F127 (PF127), and catalase (CAT)/curcumin (CUR) was co-encapsulated into these NPs. The obtained P-CUR/CAT-NPs had a hydrodynamic particle size of approximately 274.1 nm, narrow size distribution, negative zeta potential (-14.0 mV), and smooth surface morphology. Moreover, the introduction of PF127 to the surface of NPs not only facilitated their mucus penetration, but also improved their cellular uptake efficiency by the target cells (macrophages). We further found that the encapsulation of CAT could remarkably increase the release rate of CUR from NPs in the presence of an H2O2-rich environment. Additionally, P-CUR/CAT-NPs showed the strongest capacity to suppress the secretion of the main pro-inflammatory cytokines, in comparison with their counterparts (CUR-NPs and P-CUR-NPs). Importantly, oral administration of P-CAT/CUR-NPs showed the best therapeutic outcomes than the other NPs. Collectively, these results clearly demonstrate that these mucus-penetrating NPs loaded with CAT and CUR can be exploited as an efficient nanotherapeutic for UC therapy.

Is Early Spatial Skills Training Effective? A Meta-Analysis.

Spatial skills significantly predict educational and occupational achievements in science, technology, engineering, and mathematics (STEM). As early interventions for young children are usually more effective than interventions that come later in life, the present meta-analysis systematically included 20 spatial intervention studies (2009-2020) with children aged 0-8 years to provide an up-to-date account of the malleability of spatial skills in infancy and early childhood. Our results revealed that the average effect size (Hedges's g) for training relative to control was 0.96 (SE = 0.10) using random effects analysis. We analyzed the effects of several moderators, including the type of study design, sex, age, outcome category (i.e., type of spatial skills), research setting (e.g., lab vs. classroom), and type of training. Study design, sex, and outcome category were found to moderate the training effects. The results suggest that diverse training strategies or programs including hands-on exploration, visual prompts, and gestural spatial training significantly foster young children's spatial skills. Implications for research, policy, and practice are also discussed.