Tumor microenvironment-responsive degradable silica nanoparticles: design principles and precision theranostic applications.

Silica nanoparticles have emerged as promising candidates in the field of nanomedicine due to their remarkable versatility and customizable properties. However, concerns about their potential toxicity in healthy tissues and organs have hindered their widespread clinical translation. To address this challenge, significant attention has been directed toward a specific subset of silica nanoparticles, namely degradable silica nanoparticles, primarily because of their excellent biocompatibility and responsive biodegradability. In this review, we provide a comprehensive understanding of degradable silica nanoparticles, categorizing them into two distinct groups: inorganic species-doped and organic moiety-doped silica nanoparticles based on their framework components. Next, the recent progress of tumor microenvironment (TME)-responsive degradable silica nanoparticles for precision theranostic applications is summarized in detail. Finally, current bottlenecks and future opportunities of theranostic nanomedicines based on degradable silica nanoparticles in clinical applications are also outlined and discussed. The aim of this comprehensive review is to shed light on the potential of degradable silica nanoparticles in addressing current challenges in nanomedicine, offering insights into their design, applications in tumor diagnosis and treatment, and paving the way for future advancements in clinical theranostic nanomedicines.

CTLA-4 tail fusion enhances CAR-T antitumor immunity.

Chimeric antigen receptor (CAR)-T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail, we reprogram CAR function and substantially enhance CAR-T efficacy in vivo. CAR-T cells with monomeric, duplex or triplex CTLA-4 cytoplasmic tails (CCTs) fused to the C terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of proinflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior antitumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques.

Sustainable bacterial cellulose derived composites for high-efficiency hydrogen evolution reaction.

Incorporating heteroatoms into carbon structure has been demonstrated to be efficient for hydrogen evolution reaction (HER). However, the preparation complexity and poor durability are insufficient for the future hydrogen economy. In this work, the preparation of ZIF-67/BC precursor with BC as the template was done for the in-situ growth of MOFs (ZIF-67) crystals, followed by the carbonization and phosphating of ZIF-67/BC to prepare the CoP-NC/CBC N-doped composite carbon material with CoP as the primary active material. The results show that as an HER catalyst, CoP-NC/CBC can provide a current density of 10 mA cm-2 at an overpotential of 182 mV in the acidic electrolyte of 0.5 M H2SO4 or the same current density at an overpotential of 151 mV in the alkaline electrolyte of 1.0 M KOH. The work validates a design idea for advanced non-precious metal-based HER catalysts with high activity and stability.

[Functional dyspepsia treated with acupuncture of different frequencies: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy of acupuncture with different frequencies in the treatment of patients with functional dyspepsia (FD). METHODS: A total of 90 patients with FD were randomly divided into a 3-time acupuncture treatment per week group (3-A group, 31 cases, 2 cases dropped off), a 1-time acupuncture treatment per week group (1-A group, 30 cases, 2 cases dropped off) and a control group (29 cases, 2 cases dropped off). In the two acupuncture groups, the acupoints were Zhongwan (CV 12) and bilateral Tianshu (ST 25), Neiguan (PC 6), Liangqiu (ST 34), Yanglingquan (GB 34), Zusanli (ST 36) and Taichong (LR 3), stimulated 3 times a week and once a week, respectively; and the treatment was given consecutively for 4 weeks. In the control group, no intervention was adopted, but the compensatory therapy was provided after the end of follow-up. The scores of the symptom index of dyspepsia (SID), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were compared among the 3 groups before treatment, after 4 weeks of treatment and in 4 and 8 weeks after treatment completion separately. The score of Nepean dyspepsia life quality index (NDLQI) was evaluated before treatment, after 2 and 4 weeks of treatment and in 4 and 8 weeks after treatment completion. RESULTS: After 4 weeks of treatment and in 4 and 8 weeks after treatment completion, the scores of SID, SAS and SDS were all reduced in the 3-A group and the 1-A group when compared with the scores before treatment (P<0.000 1, P<0.05). After 4 weeks of treatment, the scores of SID, SAS and SDS in the two acupuncture groups were lower than those in the control group (P<0.000 1). After 2 and 4 weeks of treatment, the increased values of NDLQI score in the two acupuncture groups were all higher than those in the control group (P<0.05). In 4 and 8 weeks after treatment completion, the scores of SID, SAS and SDS in the 3-A group were lower than those in the 1-A group (P<0.001, P<0.05), and the increased values of NDLQI score in the 3-A group were higher than those in the 1-A group (P<0.000 1). CONCLUSION: Acupuncture given 3 times per week is superior to the treatment given once per week in the aspects of relieving the clinical symptoms, improving the quality of life and regulating the emotional state in patients with FD. This efficacy is persistent for 8 weeks after treatment completion.

Nanomaterials for photothermal cancer therapy.

Cancer has emerged as a pressing global public health issue, and improving the effectiveness of cancer treatment remains one of the foremost challenges of modern medicine. The primary clinical methods of treating cancer, including surgery, chemotherapy and radiotherapy, inevitably result in some adverse effects on the body. However, the advent of photothermal therapy offers an alternative route for cancer treatment. Photothermal therapy relies on photothermal agents with photothermal conversion capability to eliminate tumors at high temperatures, which offers advantages of high precision and low toxicity. As nanomaterials increasingly play a pivotal role in tumor prevention and treatment, nanomaterial-based photothermal therapy has gained significant attention owing to its superior photothermal properties and tumor-killing abilities. In this review, we briefly summarize and introduce the applications of common organic photothermal conversion materials (e.g., cyanine-based nanomaterials, porphyrin-based nanomaterials, polymer-based nanomaterials, etc.) and inorganic photothermal conversion materials (e.g., noble metal nanomaterials, carbon-based nanomaterials, etc.) in tumor photothermal therapy in recent years. Finally, the problems of photothermal nanomaterials in antitumour therapy applications are discussed. It is believed that nanomaterial-based photothermal therapy will have good application prospects in tumor treatment in the future.

Recent advances in Prussian blue-based photothermal therapy in cancer treatment.

Malignant tumours are a serious threat to human health. Traditional chemotherapy has achieved breakthrough improvements but also has significant detrimental effects, such as the development of drug resistance, immunosuppression, and even systemic toxicity. Photothermal therapy (PTT) is an emerging cancer therapy. Under light irradiation, the phototherapeutic agent converts optical energy into thermal energy and induces the hyperthermic death of target cells. To date, numerous photothermal agents have been developed. Prussian blue (PB) nanoparticles are among the most promising photothermal agents due to their excellent physicochemical properties, including photoacoustic and magnetic resonance imaging properties, photothermal conversion performance, and enzyme-like activity. By the construction of suitably designed PB-based nanotherapeutics, enhanced photothermal performance, targeting ability, multimodal therapy, and imaging-guided cancer therapy can be effectively and feasibly achieved. In this review, the recent advances in PB-based photothermal combinatorial therapy and imaging-guided cancer therapy are comprehensively summarized. Finally, the potential obstacles of future research and clinical translation are discussed.

Nanotechnological strategies to increase the oxygen content of the tumor.

Hypoxia is a negative prognostic indicator of solid tumors, which not only changes the survival state of tumors and increases their invasiveness but also remarkably reduces the sensitivity of tumors to treatments such as radiotherapy, chemotherapy and photodynamic therapy. Thus, developing therapeutic strategies to alleviate tumor hypoxia has recently been considered an extremely valuable target in oncology. In this review, nanotechnological strategies to elevate oxygen levels in tumor therapy in recent years are summarized, including (I) improving the hypoxic tumor microenvironment, (II) oxygen delivery to hypoxic tumors, and (III) oxygen generation in hypoxic tumors. Finally, the challenges and prospects of these nanotechnological strategies for alleviating tumor hypoxia are presented.

CTLA-4 tail fusion enhances CAR-T anti-tumor immunity.

Chimeric antigen receptor (CAR) T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here, utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail (CT), we reprogram CAR function and substantially enhance CAR-T efficacy in vivo . CAR-T cells with monomeric, duplex, or triplex CTLA-4 CTs (CCTs) fused to the C-terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of pro-inflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen, and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior anti-tumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques.

Cas12a/Cpf1 knock-in mice enable efficient multiplexed immune cell engineering.

Cas9 transgenic animals have drastically accelerated the discovery of novel immune modulators. But due to its inability to process its own CRISPR RNAs (crRNAs), simultaneous multiplexed gene perturbations using Cas9 remains limited, especially by pseudoviral vectors. Cas12a/Cpf1, however, can process concatenated crRNA arrays for this purpose. Here, we created conditional and constitutive LbCas12a knock-in transgenic mice. With these mice, we demonstrated efficient multiplexed gene editing and surface protein knockdown within individual primary immune cells. We showed genome editing across multiple types of primary immune cells including CD4 and CD8 T cells, B cells, and bone-marrow derived dendritic cells. These transgenic animals, along with the accompanying viral vectors, together provide a versatile toolkit for a broad range of ex vivo and in vivo gene editing applications, including fundamental immunological discovery and immune gene engineering.

Gadolinium-hybridized mesoporous organosilica nanoparticles with high magnetic resonance imaging performance for targeted drug delivery.

Magnetic resonance (MR) imaging techniques, which can provide images with excellent anatomical detail, are widely used in clinical diagnosis. However, the current clinical small molecule gadolinium (Gd) contrast agents have the defects of relatively low sensitivity and poor tumor-target specificity, preventing their adoption in biology and medicine. Herein, a facile synthetic strategy to fabricate gadolinium-hybridized mesoporous organosilica nanoparticles (MOSG) through a nanoprecipitation reaction, with the surface of nanoparticles grafted with the fluorescent dye isothiocyanate (FITC) and arginine-glycine-aspartic acid (RGD) for delivery of the antitumour drug doxorubicin hydrochloride (DOX), resulting in a high-performance nanotheranostic (RGD-MOSG-FITC/DOX) for targeted magnetic resonance imaging and chemotherapy of tumors. The prepared MOSG had a particle size of 60-80 nm and gadolinium elements were distributed in clusters that exhibited boosted longitudinal relaxivity. Routine blood tests and histopathology indicated good biocompatibility of MOSG. Furthermore, after being decorated with Arg-Gly-Asp peptide (RGD), RGD-MOSG-FITC demonstrated more preferable cellular uptake by HeLa cells (high expression of αⅤß3) than MOSG without RGD grafting. Additionally, the tumor growth inhibition effect of RGD-MOSG-FITC/DOX was substantially more effective than that of the other groups. Therefore, this new delivery platform has good application potential in the field of tumor diagnosis and treatment.

Terahertz Combined with Metamaterial Microfluidic Chip for Troponin Antigen Detection.

In this paper, we use terahertz combined with metamaterial technology as a powerful tool to identify analytes at different concentrations. Combined with the microfluidic chip, the experimental measurement can be performed with a small amount of analyte. In detecting the troponin antigen, surface modification is carried out by biochemical binding. Through the observation of fluorescent antibodies, the average number of fluorescent dots per unit of cruciform metamaterial is 25.60, and then, by adjusting the binding temperature and soaking time, the average number of fluorescent dots per unit of cruciform metamaterial can be increased to 181.02. Through the observation of fluorescent antibodies, it is confirmed that the antibodies can be successfully stabilized on the metamaterial and then bound to the target antigen. The minimum detectable concentration is between 0.05~0.1 µg/100 µL, and the concentration and ΔY show a positive correlation of R2 = 0.9909.

Genome Engineering for Next-Generation Cellular Immunotherapies.

Over the past decade, cellular immunotherapies such as CAR-T, TCR-T, and NK cell therapies have achieved tremendous success in cancer treatment. However, various challenges and obstacles remain, including antigen escape, immunosuppression in the tumor microenvironment, toxicities, and on-target off-tumor effects. Recent strategies for overcoming these roadblocks have included the use of genome engineering. Multiplexed CRISPR-Cas and synthetic biology approaches facilitate the development of cell therapies with higher potency and sophisticated modular control; they also offer a toolkit for allogeneic therapy development. Engineering approaches have targeted genetic modifications to enhance long-term persistence through cytokine modulation, knockout of genes mediating immunosuppressive signals, and genes such as the endogenous TCR and MHC-I that elicit adverse host-graft interactions in an allogeneic context. Genome engineering approaches for other immune cell types are also being explored, such as CAR macrophages and CAR-NK cells. Future therapeutic development of cellular immunotherapies may also be guided by novel target discovery through unbiased CRISPR genetic screening approaches.

Sensitivity Enhancement and Probiotic Detection of Microfluidic Chips Based on Terahertz Radiation Combined with Metamaterial Technology.

Terahertz (THz) radiation has attracted wide attention in recent years due to its non-destructive properties and ability to sense molecular structures. In applications combining terahertz radiation with metamaterial technology, the interaction between the terahertz radiation and the metamaterials causes resonance reactions; different analytes have different resonance performances in the frequency domain. In addition, a microfluidic system is able to provide low volume reagents for detection, reduce noise from the environment, and concentrate the sample on the detection area. Through simulation, a cruciform metamaterial pattern was designed; the proportion, periodicity, and width of the metamaterial were adjusted to improve the sensing capability of the chip. In the experiments, the sensing capabilities of Type A, B, and C chips were compared. The Type C chip had the most significant resonant effect; its maximum shift could be increased to 89 GHz. In the probiotic experiment, the cruciform chip could have a 0.72 GHz shift at a concentration of 0.025 mg/50 µL, confirming that terahertz radiation combined with a metamaterial microfluidic chip can perform low-concentration detection.

Tumor immunology CRISPR screening: present, past, and future.

Recent advances in immunotherapy have fundamentally changed the landscape of cancer treatment by leveraging the specificity and selectivity of the adaptive immune system to kill cancer cells. These successes have ushered in a new wave of research aimed at understanding immune recognition with the hope of developing newer immunotherapies. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) technologies and advancement of multiomics modalities have greatly accelerated the discovery process. Here, we review the current literature surrounding CRISPR screens within the context of tumor immunology, provide essential components needed to conduct immune-specific CRISPR screens, and present avenues for future research.

Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models.

Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca2+ channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor ability, and dilated cardiomyopathies, were all ameliorated by increasing ML1 activity. ML1-dependent activation of transcription factor EB (TFEB) corrects lysosomal insufficiency to diminish muscle damage. Hence, targeting lysosomal Ca2+ channels may represent a promising approach to treat DMD and related muscle diseases.

A Comprehensive Transcriptomics Analysis Reveals Long Non-Coding RNA to be Involved in the Key Metabolic Pathway in Response to Waterlogging Stress in Maize.

Waterlogging stress (WS) in a dynamic environment seriously limits plant growth, development, and yield. The regulatory mechanism underlying WS conditions at an early stage in maize seedlings is largely unknown. In the present study, the primary root tips of B73 seedlings were sampled before (0 h) and after (2 h, 4 h, 6 h, 8 h, 10 h, and 12 h) WS and then subjected to transcriptome sequencing, resulting in the identification of differentially expressed protein-coding genes (DEpcGs) and long non-coding RNAs (DElncRs) in response to WS. These DEpcGs were classified into nine clusters, which were significantly enriched in several metabolic pathways, such as glycolysis and methionine metabolism. Several transcription factor families, including AP2-EREBP, bZIP, NAC, bHLH, and MYB, were also significantly enriched. In total, 6099 lncRNAs were identified, of which 3190 were DElncRs. A co-expression analysis revealed lncRNAs to be involved in 11 transcription modules, 10 of which were significantly associated with WS. The DEpcGs in the four modules were enriched in the hypoxia response pathways, including phenylpropanoid biosynthesis, MAPK signaling, and carotenoid biosynthesis, in which 137 DElncRs were also co-expressed. Most of the co-expressed DElncRs were co-localized with previously identified quantitative trait loci associated with waterlogging tolerance. A quantitative reverse transcription-polymerase chain reaction analysis of DEpcG and DElncR expression among the 32 maize genotypes after 4 h of WS verified significant expression correlations between them as well as significant correlation with the phenotype of waterlogging tolerance. Moreover, the high proportion of hypoxia response elements in the promoter region increased the reliability of the DElncRs identified in this study. These results provide a comprehensive transcriptome in response to WS at an early stage of maize seedlings and expand our understanding of the regulatory network involved in hypoxia in plants.

Application of a Terahertz System Combined with an X-Shaped Metamaterial Microfluidic Cartridge.

Terahertz (THz) radiation has attracted wide attention for its ability to sense molecular structure and chemical matter because of a label-free molecular fingerprint and nondestructive properties. When it comes to molecular recognition with terahertz radiation, our attention goes first towards the absorption spectrum, which is beyond the far infrared region. To enhance the sensitivity for similar species, however, it is necessary to apply an artificially designed metamaterial sensor for detection, which confines an electromagnetic field in an extremely sub-wavelength space and hence receives an electromagnetic response through resonance. Once the resonance is caused through the interaction between the THz radiation and the metamaterial, a minute variation might be observed in the frequency domain. For a geometric structure of a metamaterial, a novel design called an X-shaped plasmonic sensor (XPS) can create a quadrupole resonance and lead to sensitivity greater than in the dipole mode. A microfluidic system is able to consume reagents in small volumes for detection, to diminish noise from the environment, and to concentrate the sample into detection spots. A microfluidic device integrated with an X-shaped plasmonic sensor might thus achieve an effective and highly sensitive detection cartridge. Our tests involved not only measurements of liquid samples, but also the performance of a dry bio-sample coated on an XPS.

Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels.

Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed 'S4 voltage-sensing' domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na+ channel Voltage-dependent Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies of the cell biological roles of TPCs and can also readily explain the reported effects of TCAs in the modulation of autophagy and lysosomal functions.

[Genetic analysis of ß -thalassemia mutations in the minority populations of Guizhou province].

OBJECTIVE: To investigate the gene mutation frequencies and patterns of ß-thalassemia (ß-thal) in the minority populations of Guizhou province. METHODS: Three thousand and five hundred couples in the reproductive age were screened by using automatic hemocyte analyzer and hemoglobin autoanalyzer-variant. The diagnostic criteria for ß-thal were: the mean corpuscular volume (MCV) was ≤ 82 fl, and the HbA(2) level was ≥ 3.5%. A total of 194 positive samples were detected and further identified by PCR-reverse dot blot (PCR-RDB) assay for 18 common ß -thal mutations in Chinese population. Those subjects with positive phenotypes but without the 18 common ß-thal mutations were subjected to DNA sequence analysis of the ß-globin gene. RESULTS: One hundred and eighty-nine samples with gene mutations were observed from the 3500 samples, with the incidence of ß-thal being 5.4%. A total of 10 different ß-thal mutations were identified from the 189 diagnosed samples. The five most common mutations were as the following: CD17 (43.9%), CD41-42 (38.6%), IVS-II-654(10.1%), -28 (2.6%) and CD71-72 (1.6%). In addition, a novel ß-globin gene mutation (-CD53) allele was detected. One rare mutation of IntM was observed. CONCLUSION: The minority population in Guizhou province is of high risk of ß-thal. It is recommended that more attention should be paid to detect the carriers of ß-thal in the population in reproductive age by hematologic screening and common gene diagnosis in the area with high risk of ß-thal.