Metal-Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells.

Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal-organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells' membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating •O2-, and the Cu-THBQ/AX catalyzes O2 and H2O2 to •O2- and •OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of •OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from "cold" to "hot" conditions, making it an effective antigen pool. This transformation successfully activates the antitumor immune response, inhibiting tumor growth and metastasis.

Cooperative supramolecular polymerization of styrylpyrenes for color-dependent circularly polarized luminescence and photocycloaddition.

Developing facile and efficient methods to obtain circularly polarized luminescence (CPL) materials with a large luminescence dissymmetry factor (glum) and fluorescence quantum yield (ΦY) is attractive but still challenging. Herein, supramolecular polymerization of styrylpyrenes (R/S-PEB) is utilized to attain this aim, which can self-assemble into helical nanoribbons. Benefiting from the dominant CH-π interactions between the chromophores, the supramolecular solution of S-PEB shows remarkable blue-color CPL property (glum: 0.011, ΦY: 69%). From supramolecular solution to gel, the emission color (blue to yellow-green) and handedness of CPL (glum: -0.011 to +0.005) are concurrently manipulated, while the corresponding supramolecular chirality maintains unchanged, representing the rare example of color-dependent CPL materials. Thanks to the supramolecular confine effect, the [2 + 2] cycloaddition reaction rate of the supramolecular solution is 10.5 times higher than that of the monomeric solution. In contrast, no cycloaddition reaction occurs for the gel and assembled solid samples. Our findings provide a vision for fabricating multi-modal and high-performance CPL-active materials, paving the way for the development of advanced photo-responsive chiral systems.

Nanocompartment-confined polymerization in living systems.

Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p­aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.

Cucurbit[8]uril-based water-dispersible assemblies with enhanced optoacoustic performance for multispectral optoacoustic imaging.

Organic small-molecule contrast agents have attracted considerable attention in the field of multispectral optoacoustic imaging, but their weak optoacoustic performance resulted from relatively low extinction coefficient and poor water solubility restrains their widespread applications. Herein, we address these limitations by constructing supramolecular assemblies based on cucurbit[8]uril (CB[8]). Two dixanthene-based chromophores (DXP and DXBTZ) are synthesized as the model guest compounds, and then included in CB[8] to prepare host-guest complexes. The obtained DXP-CB[8] and DXBTZ-CB[8] display red-shifted and increased absorption as well as decreased fluorescence, thereby leading to a substantial enhancement in optoacoustic performance. Biological application potential of DXBTZ-CB[8] is investigated after co-assembly with chondroitin sulfate A (CSA). Benefiting from the excellent optoacoustic property of DXBTZ-CB[8] and the CD44-targeting feature of CSA, the formulated DXBTZ-CB[8]/CSA can effectively detect and diagnose subcutaneous tumors, orthotopic bladder tumors, lymphatic metastasis of tumors and ischemia/reperfusion-induced acute kidney injury in mouse models with multispectral optoacoustic imaging.

Microbial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy.

Cancer immunotherapy is revolutionizing oncology. The marriage of nanotechnology and immunotherapy offers a great opportunity to amplify antitumor immune response in a safe and effective manner. Here, electrochemically active Shewanella oneidensis MR-1 can be applied to produce FDA-approved Prussian blue nanoparticles on a large-scale. We present a mitochondria-targeting nanoplatform, MiBaMc, which consists of Prussian blue decorated bacteria membrane fragments having further modifications with chlorin e6 and triphenylphosphine. We find that MiBaMc specifically targets mitochondria and induces amplified photo-damages and immunogenic cell death of tumor cells under light irradiation. The released tumor antigens subsequently promote the maturation of dendritic cells in tumor-draining lymph nodes, eliciting T cell-mediated immune response. In two tumor-bearing mouse models using female mice, MiBaMc triggered phototherapy synergizes with anti-PDL1 blocking antibody for enhanced tumor inhibition. Collectively, the present study demonstrates biological precipitation synthetic strategy of targeted nanoparticles holds great potential for the preparation of microbial membrane-based nanoplatforms to boost antitumor immunity.

In situ generation of micrometer-sized tumor cell-derived vesicles as autologous cancer vaccines for boosting systemic immune responses.

Cancer vaccine, which can promote tumor-specific immunostimulation, is one of the most important immunotherapeutic strategies and holds tremendous potential for cancer treatment/prevention. Here, we prepare a series of nanoparticles composed of doxorubicin- and tyrosine kinase inhibitor-loaded and hyaluronic acid-coated dendritic polymers (termed HDDT nanoparticles) and find that the HDDT nanoparticles can convert various cancer cells to micrometer-sized vesicles (1.6-3.2 µm; termed HMVs) with ~100% cell-to-HMV conversion efficiency. We confirm in two tumor-bearing mouse models that the nanoparticles can restrain tumor growth, induce robust immunogenic cell death, and convert the primary tumor into an antigen depot by producing HMVs in situ to serve as personalized vaccines for cancer immunotherapy. Furthermore, the HDDT-healed mice show a strong immune memory effect and the HDDT treatment can realize long-term protection against tumor rechallenge. Collectively, the present work provides a general strategy for the preparation of tumor-associated antigen-containing vesicles and the development of personalized cancer vaccines.

Effect of Acupuncture along Meridians on Pain Degree and Treatment of Acute Lumbar Sprain.

Aim: This study is aimed at investigating the effect of acupuncture along meridians on pain degree and treatment of acute lumbar sprain. Methods: A total of 96 patients with acute lumbar sprain from May 2019 to March 2021 in our hospital were selected and divided into the study and control groups. The patients in the control group were administered conventional western medicine and massage therapy, while the study group underwent acupuncture along meridians based on the control group. The therapeutic effect, visual analogue scale (VAS), Roland-Morris Disability Questionnaire (RMDQ), and lumbar range of motion (ROM) scores, emG inversion times, emG amplitude of the sacrospinalis muscle, and the serum TNF-α and IL-6 levels were determined. Results: The total effective rate of the study group was significantly higher than that of the control group. After treatment, the VAS, RMDQ, and ROM scores of the study group were significantly lower than those of the control group. Before the intervention, the EMG inversion times and the EMG amplitude of the spinous process muscle in the study group were not significantly different from those in the control group. After the intervention, the number and amplitude of EMG reversal in the study group were significantly higher than those in the control group. After the intervention, the serum levels of TNF-α (pg/ml) and IL-6 (pg/ml) in the study group were significantly lower than those in the control group. Conclusion. Meridian acupuncture for acute lumbar sprain can effectively improve body function, relieve pain, regulate serum inflammatory factors, and improve the overall therapeutic effect.

The clinical effects of brain-computer interface with robot on upper-limb function for post-stroke rehabilitation: a meta-analysis and systematic review.

PURPOSE: Many recent clinical studies have suggested that the combination of brain-computer interfaces (BCIs) can induce neurological recovery and improvement in motor function. In this review, we performed a systematic review and meta-analysis to evaluate the clinical effects of BCI-robot systems. METHODS: The articles published from January 2010 to December 2020 have been searched by using the databases (EMBASE, PubMed, CINAHL, EBSCO, Web of Science and manual search). The single-group studies were qualitatively described, and only the controlled-trial studies were included for the meta-analysis. The mean difference (MD) of Fugl-Meyer Assessment (FMA) scores were pooled and the random-effects model method was used to perform the meta-analysis. The PRISMA criteria were followed in current review. RESULTS: A total of 897 records were identified, eight single-group studies and 11 controlled-trial studies were included in our review. The systematic analysis indicated that the BCI-robot systems had a significant improvement on motor function recovery. The meta-analysis showed there were no statistic differences between BCI-robot groups and robot groups, neither in the immediate effects nor long-term effects (p > 0.05). CONCLUSION: The use of BCI-robot systems has significant improvement on the motor function recovery of hemiparetic upper-limb, and there is a sustaining effect. The meta-analysis showed no statistical difference between the experimental group (BCI-robot) and the control group (robot). However, there are a few shortcomings in the experimental design of existing studies, more clinical trials need to be conducted, and the experimental design needs to be more rigorous.Implications for RehabilitationIn this review, we evaluated the clinical effects of brain-computer interface with robot on upper-limb function for post-stroke rehabilitation. After we screened the databases, 19 articles were included in this review. These articles all clinical trial research, they all used non-invasive brain-computer interfaces and upper-limb robot.We conducted the systematic review with nine articles, the result indicated that the BCI-robot system had a significant improvement on motor function recovery. Eleven articles were included for the meta-analysis, the result showed there were no statistic differences between BCI-robot groups and robot groups, neither in the immediate effects nor long-term effects.We thought the result of meta-analysis which showed no statistic difference was probably caused by the heterogenicity of clinical trial designs of these articles.We thought the BCI-robot systems are promising strategies for post-stroke rehabilitation. And we gave several suggestions for further research: (1) The experimental design should be more rigorous, and describe the experimental designs in detail, especially the control group intervention, to make the experiment replicability. (2) New evaluation criteria need to be established, more objective assessment such as biomechanical assessment, fMRI should be utilised as the primary outcome. (3) More clinical studies with larger sample size, novel external devices, and BCI systems need to be conducted to investigate the differences between BCI-robot system and other interventions. (4) Further research could shift the focus to the patients who are in subacute stage, to explore if the early BCI training can make a positive impact on cerebral cortical recovery.

Nanozymes: Versatile Platforms for Cancer Diagnosis and Therapy.

Natural enzymes usually suffer from high production cost, ease of denaturation and inactivation, and low yield, making them difficult to be broadly applicable. As an emerging type of artificial enzyme, nanozymes that combine the characteristics of nanomaterials and enzymes are promising alternatives. On the one hand, nanozymes have high enzyme-like catalytic activities to regulate biochemical reactions. On the other hand, nanozymes also inherit the properties of nanomaterials, which can ameliorate the shortcomings of natural enzymes and serve as versatile platforms for diverse applications. In this review, various nanozymes that mimic the catalytic activity of different enzymes are introduced. The achievements of nanozymes in different cancer diagnosis and treatment technologies are summarized by highlighting the advantages of nanozymes in these applications. Finally, future research directions in this rapidly developing field are outlooked.

Feature optimization based on improved novel global harmony search algorithm for motor imagery electroencephalogram classification.

Background: Effectively decoding electroencephalogram (EEG) pattern for specific mental tasks is a crucial topic in the development of brain-computer interface (BCI). Extracting common spatial pattern (CSP) features from motor imagery EEG signals is often highly dependent on the selection of frequency band and time interval. Therefore, optimizing frequency band and time interval would contribute to effective feature extraction and accurate EEG decoding. Objective: This study proposes an approach based on an improved novel global harmony search (INGHS) to optimize frequency-time parameters for effective CSP feature extraction. Methods: The INGHS algorithm is applied to find the optimal frequency band and temporal interval. The linear discriminant analysis and support vector machine are used for EEG pattern decoding. Extensive experimental studies are conducted on three EEG datasets to assess the effectiveness of our proposed method. Results: The average test accuracy obtained by the time-frequency parameters selected by the proposed INGHS method is slightly better than artificial bee colony (ABC) and particle swarm optimization (PSO) algorithms. Furthermore, the INGHS algorithm is superior to PSO and ABC in running time. Conclusion: These superior experimental results demonstrate that the optimal frequency band and time interval selected by the INGHS algorithm could significantly improve the decoding accuracy compared with the traditional CSP method. This method has a potential to improve the performance of MI-based BCI systems.

Thiolate-Assisted Route for Constructing Chalcogen Quantum Dots with Photoinduced Fluorescence Enhancement.

Despite great efforts in the development of diverse nanomaterials, a general route to synthesize metal-free chalcogen quantum dots (QDs) is still lacking. Moreover, the modification of chalcogen QDs is a bottleneck that severely hinders their applications. Herein, we develop a facile method to construct different chalcogen QDs (including S QDs, Se QDs, and Te QDs) with the assistance of thiolates. In addition to stabilizing chalcogen QDs, the thiolates also endow the chalcogen QDs with favorable modifiability. Different from most dyes whose fluorescence is quenched after short-term light irradiation, the prepared chalcogen QDs have significantly enhanced fluorescence emission under continuous light irradiation. Taking advantage of the distinctive photoinduced fluorescence enhancement property, long-time cell imaging with superb performance is realized using the chalcogen QDs. It is envisioned that the chalcogen QDs show promising potential as fluorescent materials in different fields beyond bioimaging.

Rationally designed upconversion nanoparticles for NIR light-controlled lysosomal escape and nucleus-based photodynamic therapy.

Cell nucleus-based photodynamic therapy is a highly effective method for cancer therapy, but it is still challenging to design nucleus-targeting photosensitizers. Here, we propose the "one treatment, multiple irradiations" strategy to achieve nucleus-based photodynamic therapy using the photosensitizer rose bengal (RB)-loaded and mesoporous silica-coated upconversion nanoparticles with the surface modification of amine group (UCNP/RB@mSiO2-NH2 NPs). After implementation into cancer cells, the rationally designed UCNP/RB@mSiO2-NH2 NPs could be specifically accumulated in the acidic lysosomes due to their amino group-decorated surface. Upon a short-term (3 min) irradiation of 980 nm near-infrared light, the reactive oxygen species produced by RB through the Förster resonance energy transfer between the upconversion nanoparticles and RB molecules could effectively destroy lysosomes, followed by the release of the UCNP/RB@mSiO2-NH2 NPs from the lysosomes. Subsequently, these released UCNP/RB@mSiO2-NH2 NPs could be transferred into the cell nucleus, where a second 980 nm light irradiation was conducted to achieve the nucleus-based photodynamic therapy. The rationally designed UCNP/RB@mSiO2-NH2 NPs showed excellent anticancer performance in both two-dimensional and three-dimensional cell models using the "one treatment, multiple irradiations" strategy.

Missing-Linker-Assisted Artesunate Delivery by Metal-Organic Frameworks for Synergistic Cancer Treatment.

Clinical translation of artesunate (ATS) as a potent antitumor drug has been obstructed by its rapid degradation and low bioavailability. Herein, we report the development of an ATS nanomedicine through the self-assembly with Mn[Co(CN)6 ]2/3 □1/3 metal-organic frameworks (MOFs) that have hidden missing linkers. The defects in MOFs originating from the missing linkers play a key role in increasing the biological stability and tumor accumulation of ATS. Chlorin e6 (Ce6) and ATS can be co-loaded into MOFs for a synergistic antitumor efficacy. In the presence of intracellular HCO3- , Mn2+ acts as an efficient catalyst to promote the bicarbonate-activated H2 O2 system which oxidizes ATS to generate reactive oxygen species and induce oxidative death to cancer cells. The released [CoIII (CN)6 ] linker undergoes a redox reaction with intracellular glutathione to prevent the scavenging ability of reactive oxygen species, contributing to synergistic chemodynamic therapy of ATS and photodynamic therapy of Ce6. Thus, defect-engineered MOFs with hidden missing linkers hold great promise in advancing the practical use of ATS as an antitumor medicine.

Dual Gate-Controlled Therapeutics for Overcoming Bacterium-Induced Drug Resistance and Potentiating Cancer Immunotherapy.

The presence of bacteria in the tumor can cause cancer resistance to chemotherapeutics. To fight against bacterium-induced drug resistance, herein we design self-traceable nanoreservoirs that are simultaneously loaded with gemcitabine (an anticancer drug) and ciprofloxacin (an antibiotic) and are decorated with hyaluronic acid for active tumor targeting. The nanoreservoirs have a pH-sensitive gate and an enzyme-responsive gate that can be opened in the acidic and hyaluronidase-abundant tumor microenvironment to control drug release rates. Moreover, the nanoreservoirs can specifically target the tumor regions without eliciting evident toxicity to normal tissues, kill the intratumoral bacteria, and inhibit the tumor growth even in the presence of the bacteria. Unexpectedly, the nanoreservoirs can activate T cell-mediated immune responses through promoting antigen-presenting dendritic cell maturation and depleting immunosuppressive myeloid-derived suppressor cells in bacterium-infected tumors.

Optimized acupuncture treatment (acupuncture and intradermal needling) for cervical spondylosis-related neck pain: a multicenter randomized controlled trial.

ABSTRACT: Cervical spondylosis (CS)-related neck pain is difficult to treat because of its degenerative nature. The aim of this 9-center, single-blinded, randomized controlled trial was to evaluate the efficacy of optimized acupuncture for CS-related neck pain. Participants who met the inclusion criteria were randomized to optimized, shallow, and sham acupuncture groups (1:1:1). The primary outcome was the change from baseline in the Northwick Park Neck Pain Questionnaire score at week 4. Participants were followed up until week 16. Of the 896 randomized participants, 857 received ≥1 intervention session; 280, 286, and 291 received optimized, shallow, and sham acupuncture, respectively. A total of 835 (93.2%) participants completed the study. At week 4, significant differences (P < 0.001) were observed in the changes in Northwick Park Neck Pain Questionnaire scores between the optimized acupuncture group and both the shallow {7.72 (95% confidence interval [CI], 5.57-9.86)} and sham acupuncture (10.38 [95% CI, 8.25-12.52]) groups. The difference in the scores at week 16 between the optimized acupuncture group and the shallow (8.84 [95% CI, 6.34-11.34]) and sham acupuncture (10.81 [95% CI, 8.32-13.30]) groups were significant. The center effect indicated wide variability in the treatment effects (Cohen's d = 0.01-2.19). Most SF-36 scores were higher in the optimized acupuncture group than those in the other groups. These results suggest that 4-week optimized acupuncture treatment alleviates CS-related neck pain and improves the quality of life, with the effects persisting for minimum 3 months. Therefore, acupuncture can have positive effects on CS-related neck pain, although the effect size may vary widely.

Size-Transformable Nanostructures: From Design to Biomedical Applications.

The size of nanostructures (NSs) strongly affects their chemical and physical properties and further impacts their actions in biological systems. Both small and large NSs possess respective advantages for disease theranostics, and this therefore presents a paradox when choosing NSs with suitable sizes. To overcome this challenge, size-transformable NSs have emerged as a powerful tool, as they can be manipulated to possess the merits of both types of NSs. Herein, various strategies to construct size-transformable NSs are summarized, and the recent research progress regarding their biomedical applications, particularly within the fields of cancer and bacterial theranostics, is highlighted. This review will inspire researchers to further develop various methods that can be used to construct size-transformable NSs for use in novel applications within different fields.

Pore Structure and Fractal Characteristic Analysis of Gasification-Coke Prepared at Different High-Temperature Residence Times.

An accurate and quantitative description of the pore structure of gasification-coke using fractal geometry could be of great significance to its industrial utilization. In this study, gasification-coke was prepared with low-quality coal blending at different high-temperature residence times to investigate the variation in the pore structure, fractal dimensions, reactivities, and their relationship. The pore structure parameters (e.g., specific surface area, pore volume, and average pore diameter) of gasification-coke were investigated by low-temperature N2 adsorption/desorption and mercury intrusion porosimetry. Fractal dimensions D 1 and D 2 (at relative pressures of 0-0.5 and 0.5-1, respectively) were calculated using the fractal Frenkel-Halsey-Hill model, and the fractal dimension D 3 was obtained using the Menger sponge model. The results show that the pore structure systems of gasification-coke prepared at different high-temperature residence times are continuous and complete, which contributes to the gasification reaction. The variation trend of the macropore structure parameters is more complex than that of micropore and mesopore with the extension of the high-temperature residence time. It is found that D 1 is linearly correlated with the micropore specific surface area, indicating that D 1 is more suitable for reflecting the roughness of the micropore surface; D 2 is linearly correlated with the mesopore volume and can describe the volumetric roughness of the mesopore; and D 3 reflects the irregularities and surface roughness of the macropores. Gasification reactivity is closely related to the D 2 value, and the reactivity of the gasification-coke may be improved if the number of mesopores is increased by controlling the high-temperature residence time or other pyrolysis conditions. The research results will provide theoretical reference for controlling the gasification reaction of gasification-coke and gasifier design.

Endosome/lysosome-detained supramolecular nanogels as an efflux retarder and autophagy inhibitor for repeated photodynamic therapy of multidrug-resistant cancer.

The presence of drug efflux pumps and endo/lysosomal entrapment phenomena in multidrug-resistant cancer cells leads to insufficient and off-target accumulation of anticancer drugs in the cells, which severely reduces the drugs' therapeutic efficacies. Here, we prepare a novel type of photosensitizer (PS)-loaded supramolecular nanogel, which can utilize the endo/lysosomal entrapment for enhanced photodynamic therapy (PDT) of multidrug-resistant cancer. The PS-loaded nanogels can elude the drug efflux pumps, and be markedly internalized by drug-resistant cancer cells through the endocytic pathway. With their pH-sensitive properties, the internalized nanogels can aggregate in the acidic endosomes/lysosomes, thus retarding their exocytosis from the cells. Moreover, the lysosomes of the nanogel-treated cells are severely damaged after irradiation, which inhibits the protective autophagy and improves the photodynamic therapeutic performance of the nanogels. Besides, the in vivo experiments show that the nanogels significantly prolong the tumor retention of the PSs, thus enabling multiple PDT treatments after a single drug injection.

Indoor air formaldehyde (HCHO) pollution of urban coach cabins.

Urban coach cabin is an important indoor environment for long journey, formaldehyde (HCHO) is a carcinogenic gas and damages indoor air quality of cabins. In order to control the HCHO pollution, the air samples inside cabins were analysed with a thermally desorbed gas chromatograph, and the HCHO diffusion was simulated with a methodology of computational fluid dynamics (CFD). Results show that through the experimental monitoring, the HCHO pollution level range from 33.6 to 142.3 µg/m3, decrease quickly with time, and the attenuation trendline is univariate cubic equation. Through the CFD simulation, the indoor temperature and HCHO level of cabin front and rear ends are higher than ones of other areas for the insufficient air supply and the unreasonable arrangement of air exhaust outlet. Moreover, through the CFD simulation, the HCHO level decreases with height growth of breathing zone and increasing air supply speed, and fresh air lead to diffusion of HCHO pollution from cabin seat area to the surrounding area. Through the CFD simulation, the HCHO pollution under the wind speeds of 3~5 m/s is higher than the HCHO limit level from indoor air standard of China vehicles, which shows that the HCHO emission of cabin seat has an important impact on airborne HCHO pollution inside vehicle cabins.