Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

Catalytic activity and mechanism of F- and Cl-doped graphene for peroxymonosulfate activation to remove tetracycline hydrochloride.

Highly active catalysts with salt and acid/alkali resistance are desired in peroxymonosulfate (PMS) activation processes and marine environment applications. F- and Cl-doped graphene (F-GN and Cl-GN) were prepared via electronegative and atom radius adjustment for tetracycline hydrochloride (TCH) pollution removal to satisfy these requirements. The introduction of special F and Cl functionalities into graphene exhibits superior electron transfer properties for PMS activation, considering the experimental and density functional theory (DFT) calculation results. The TCH degradation efficiency reached up to 80% under various pH and salt disturbance conditions with F-GN and Cl-GN. Cl-GN exhibited an activity superior to F-GN due to the higher electron polarization effect of C atoms adjacent to Cl atoms. The presence of more positive charged C sites in Cl-GN (around Cl doping) is more favorable for PMS attachment and sequence radical generation than F-GN. In addition, the main active species functionalized during reaction included ·OH and SO4-·, and the stability of F-GN and Cl-GN was confirmed to be over 60% by recycle test. Final research results provide an effective strategy for designing and preparing PMS activators resistant to salt, acid, and alkali, thereby expanding their application potential.

Orally Administrated Hydrogel Harnessing Intratumoral Microbiome and Microbiota-Related Immune Responses for Potentiated Colorectal Cancer Treatment.

The intestinal and intratumoral microbiota are closely associated with tumor progression and response to antitumor treatments. The antibacterial or tumor microenvironment (TME)-modulating approaches have been shown to markedly improve antitumor efficacy, strategies focused on normalizing the microbial environment are rarely reported. Here, we reported the development of an orally administered inulin-based hydrogel with colon-targeting and retention effects, containing hollow MnO2 nanocarrier loaded with the chemotherapeutic drug Oxa (Oxa@HMI). On the one hand, beneficial bacteria in the colon specifically metabolized Oxa@HMI, resulting in the degradation of inulin and the generation of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in modulating microbiota and stimulating immune responses. On the other hand, the hydrogel matrix underwent colon microbiota-specific degradation, enabling the targeted release of Oxa and production of reactive oxygen species in the acidic TME. In this study, we have established, for the first time, a microbiota-targeted drug delivery system Oxa@HMI that exhibited high efficiency in colorectal cancer targeting and colon retention. Oxa@HMI promoted chemotherapy efficiency and activated antitumor immune responses by intervening in the microbial environment within the tumor tissue, providing a crucial clinical approach for the treatment of colorectal cancer that susceptible to microbial invasion.

Construction Strategy of Functionalized Liposomes and Multidimensional Application.

Liposomes are widely used in the biological field due to their good biocompatibility and surface modification properties. With the development of biochemistry and material science, many liposome structures and their surface functional components have been modified and optimized one by one, pushing the liposome platform from traditional to functionalized and intelligent, which will better satisfy and expand the needs of scientific research. However, a main limiting factor effecting the efficiency of liposomes is the complicated environmental conditions in the living body. Currently, in order to overcome the above problem, functionalized liposomes have become a very promising strategy. In this paper, binding strategies of liposomes with four main functional elements, namely nucleic acids, antibodies, peptides, and stimuli-responsive motif have been summarized for the first time. In addition, based on the construction characteristics of functionalized liposomes, such as drug-carrying, targeting, long-circulating, and stimulus-responsive properties, a comprehensive overview of their features and respective research progress are presented. Finally, the paper critically presents the limitations of these functionalized liposomes in the current applications and also prospectively suggests the future development directions, aiming to accelerate realization of their industrialization.

Elucidating the roles of Ni ions and crosslinking heteroatoms in Ni3(BHT)2/2GO as electron shuttles for electrocatalytic oxidation of tetracycline hydrochloride.

As a hot candidate for marine pollution control, electrocatalytic oxidation strongly depends on the characteristics of anode materials. Even though emerging 2D metal-organic frameworks (2D-MOFs)/graphene oxide (GO) complex has satisfied the conductive and tunable requirements of anode, electrocatalytic efficiency still needs to be improved by maximizing the electron carriers or shuttles. Herein, we capitalized upon crosslinking heteroatoms as pointcut to adjust the electron distribution, mobility, and transfer orientation in 2D-MOFs/GO. As a result, Ni3(BHT)2/2GO (metal centers: Ni; crosslinking heteroatoms: S), which was much higher than materials with metal centers of Cu or crosslinking heteroatoms of N, achieved superior conductivity and 100% tetracycline hydrochloride removal within 12 min. In Ni3(BHT)2/2GO, Ni ions and S atoms cooperated as electron shutters rather than isolated active center and granted accelerated electron transfer from 2D-MOFs to GO layers. Furthermore, Ni sites and S crosslinking heteroatoms exhibited superior activity for ⋅O2- and ⋅OH generation, whereas 1O2 depended more on C and O substrates. All experiments, theory calculations, and application expanding approved the practice feasibility of 2D-MOFs/GO in electrocatalytic oxidation by adjusting crosslinking heteroatoms. All these results provided new perspectives on the micro-molecular regulation for improving electrocatalytic efficiency.

Research progress of All-in-One PCR tube biosensors based on functional modification and intelligent fabrication.

PCR amplification technology is the cornerstone of molecular biology. All-in-One PCR tube, as an emerging integrated device, is booming in biosensors application. All-in-One PCR tube biosensors are integrated PCR tubes designed for signal recognition, signal amplification or signal output. They enable "one-pot" detection within functionally modified and intelligently fabricated PCR tubes, effectively overcoming the limitations of conventional PCR applications, like complex procedural steps, risk of contamination and so on. Based on this, the review article summarizes the recent advance of All-in-One PCR tube biosensors for the first time as well as systematically categorizes five approaches of functional modification, three types of intelligent fabrication and relevant property characterization techniques. More emphasis is placed on the review of five ways of functional modification, including physical modification, chemical modification, UV photografting surface treatment, plasma surface modification, and layer-by-layer assembly coating. Moreover, All-in-One PCR tube biosensors covering different recognition elements range from small molecules to protein are detailed discussed on principle of sensing, providing a deeper understanding of the design and application of All-in-One-tube biosensor. Last, the future opportunities and challenges in this fascinating field are also deliberated.

Modulating Cu valence state in Cu and graphene oxide composites for electrocatalytic tetracycline hydrochloride degradation.

Cu and graphene oxide composites (Cu-GO) were designed by anchoring Cu+ via oxygen groups in GO based on the heavy co-relationships of copper (Cu) anode electrocatalytic activity with Cu valence state. With the consumption of oxygen groups under various pyrolysis temperatures, the Cu valence state changed from Cu ions (as CuCl2 and CuCl) to Cu oxide (CuO and Cu2O) and the final metallic Cu. In which the Cu+ in CuCl was more favorable for electrocatalytic oxidation than other Cu valence states. Due to the dramatic contribution of 1O2 and active chlorine, 100% degradation efficiency was achieved using tetracycline hydrochloride (TCH) as the target pollutant. Cu+ showed a selective preference for 1O2 and active chlorine triggering, rather than metallic Cu. Under the attack of 1O2 and active chlorine, the degradation intermediates of TCH were then provided by LC-MS results. The final results not only prove the feasibility of the Cu-GO/electrocatalysis system for pollution control but also shed light on the anode design via Cu valence state modulation.

Microstructure and Mechanical Behavior of Quaternary Eutectic α+θ+Q+Si Clusters in As-Cast Al-Mg-Si-Cu Alloys.

Cu additions notably strengthen Al-Mg-Si and Al-Si-Mg alloys due to the dense precipitation of quaternary nano precipitates during ageing. However, the chemical evolution and mechanical behaviors of the quaternary micro-scale Q constituent phase occurring in cast and homogenized states have rarely been studied. Meanwhile, there exists a type of AlCuMgSi cluster in the cast state, which has been regarded as Q particles. The accurate identification of phase constituents is the basis for the future design of alloys with better performance. In our work, this type of cluster was revealed to consist of α-Al, θ-Al2Cu, Q, and Si phases through micro-to-atomic scale studies using scanning and transmission electron microscopes. The skeleton of the dendrite was θ phase. The second phases in the dendritic eutectic cluster dissolved quickly during a 4 h homogenization at 550 °C. The Q phase was found to effectively absorb the Fe impurities during casting and homogenization. As a result, the formation of other harmful Fe-rich intermetallics was suppressed. These Q constituent particles were observed to break into separate pieces in an intermediately brittle manner when compressed in situ in a scanning electron microscope. These findings provide insights into the thermodynamic modeling of the Al-Mg-Si-Cu system and alloy design.

Proteins rather than mRNAs regulate nucleation and persistence of Oskar germ granules in Drosophila.

RNA granules are membraneless condensates that provide functional compartmentalization within cells. The mechanisms by which RNA granules form are under intense investigation. Here, we characterize the role of mRNAs and proteins in the formation of germ granules in Drosophila. Super-resolution microscopy reveals that the number, size, and distribution of germ granules is precisely controlled. Surprisingly, germ granule mRNAs are not required for the nucleation or the persistence of germ granules but instead control their size and composition. Using an RNAi screen, we determine that RNA regulators, helicases, and mitochondrial proteins regulate germ granule number and size, while the proteins of the endoplasmic reticulum, nuclear pore complex, and cytoskeleton control their distribution. Therefore, the protein-driven formation of Drosophila germ granules is mechanistically distinct from the RNA-dependent condensation observed for other RNA granules such as stress granules and P-bodies.

Synergy of multiple precipitate/matrix interface structures for a heat resistant high-strength Al alloy.

High strength aluminum alloys are widely used but their strength is reduced as nano-precipitates coarsen rapidly in medium and high temperatures, which greatly limits their application. Single solute segregation layers at precipitate/matrix interfaces are not satisfactory in stabilizing precipitates. Here we obtain multiple interface structures in an Al-Cu-Mg-Ag-Si-Sc alloy including Sc segregation layers, C and L phases as well as a newly discovered χ-AgMg phase, which partially cover the θ' precipitates. By atomic resolution characterizations and ab initio calculations, such interface structures have been confirmed to synergistically retard coarsening of precipitates. Therefore, the designed alloy shows the good combination of heat resistance and strength among all series of Al alloys, with 97% yield strength retained after thermal exposure, which is as high as 400 MPa. This concept of covering precipitates with multiple interface phases and segregation layers provides an effective strategy for designing other heat resistant materials.

Coordination-Driven One-Step Rapid Self-Assembly Synthesis of Dual-Functional Ag@Pt Nanozyme.

Realizing high-precise and adjustable regulation of engineering nanozyme is important in nanotechnology. Here, Ag@Pt nanozymes with excellent peroxidase-like and antibacterial effects are designed and synthesized by nucleic acid and metal ions coordination-driven one-step rapid self-assembly. The adjustable NA-Ag@Pt nanozyme is synthesized within 4 min using single-stranded nucleic acid as templates, and peroxidase-like enhancing FNA-Ag@Pt nanozyme is received by regulating functional nucleic acids (FNA) based on NA-Ag@Pt nanozyme. Both Ag@Pt nanozymes that are developed not only has simple and general synthesis approaches, but also can produce artificial precise adjustment and possess dual-functional. Moreover, when lead ion-specific aptamers as FNA are introduced to NA-Ag@Pt nanozyme, the Pb2+ aptasensor is successfully constructed by increasing electron conversion efficiency and improving the specificity of nanozyme. In addition, both nanozyme has good antibacterial properties, with ~100% and ~85% antibacterial efficiency against Escherichia coli and Staphylococcus aureus, respectively. This work provides a synthesis method of novelty dual-functional Ag@Pt nanozymes and successful application in metal ions detection and antibacterial agents.

Cavity hairpin ThT-light nucleic acid switches: the construction of label- and enzyme-free sensing and imaging platforms.

Thioflavin T (ThT) is a classical fluorescent dye gaining prominence in current research regarding nucleic acid conformations (NACs). However, most NACs with the ability to excite ThT fluorescent are unique or form in demanding conditions, limiting the extensiveness and depth of ThT application in sensing and imaging. Therefore, this study proposed CGG-AAA mismatched cavity hairpin ThT-light nucleic acid switches (CHTLNAS) with excellent fluorescence excitation over 500-fold higher than spontaneous, 17∼20-fold higher than ssDNA and 2.5∼5-fold higher than complementary duplex. Based on the excellent fluorescence excitation, convenient conformation formation, good sequence programmability, and flexible allosteric ability (known as the Worm-crack pod mechanism mediated by the target), it achieved the label- and enzyme-free detection of tetracycline (TET) and berberine (BB) at the pM level within 10 min. Moreover, it was found enable to realize the sensitive tracking of intracellular carriers at the nM level of ThT entry concentration, and prolongated its cell nuclear-entry time of ThT over 8 h, overcoming the non-specific high background signal interference of ThT in the nuclear region, and expanding the diversified application of ThT in cell biology research. Therefore, CHTLNAS is a more universal, practical tool than G-quadruplex or other kinds of NACs for ThT development and utilization in sensing and imaging platforms.

Docking-aided rational tailoring of a fluorescence- and affinity-enhancing aptamer for a label-free ratiometric malachite green point-of-care aptasensor.

Although nucleic acid aptasensors are increasingly applied in the detection of environmentally hazardous biomolecules, several formidable challenges remain with this technique because of their vulnerability, high cost and suboptimal sensitivity. Here, a docking-aided rational tailoring (DART) strategy was established at three levels and in two dimensions for the refinement of malachite green (MG) DNA aptamers. Guided by in silico molecular docking, coarse and fine tailoring were conducted at three levels each, to significantly enhance fluorescence activation intensity and binding affinity in two dimensions. Empowered by the results of the rational tailoring, a mechanistic view of the MG DNA aptamer-target interaction was thoroughly analyzed via four types of interactions. To meet the demand for point-of-care testing (POCT), a label-free and ratiometric fluorescent aptasensor was developed leveraging the tailored MG aptamer, based on the binding site competition-equilibrium effect via the introduction of a reference dye. This sensitive, specific, low-cost and rapid aptasensor subsequently demonstrated outstanding detection performance, achieving an ideal signal response range of 5 nmol·L-1 - 6 µmol·L-1 and a low limit of detection (LOD) of 1.49 nmol·L-1. The DART strategy and systematic exploration of the MG DNA luminescent aptamers herein will provide a valuable reference in the field of aptamer tailoring, biosensing and bioimaging. The proposed label-free ratiometric aptasensor also provides a highly generalizable strategy for hazardous biomolecular detection.

One-Pot Controllable Assembly of a Baicalin-Condensed Aptamer Nanodrug for Synergistic Anti-Obesity.

The rapid, simple and low-cost preparation of DNA micro-nano-architectures remain challenging in biosensing and therapy. Polymerase chain reaction (PCR)-driven DNA micro-nano-flowers are used to construct a nanosized baicalin-compressed-aptamer-nanodrug (bcaND) via one-pot assembly for targeted and synergistic anti-obesity. In the design, the tailored Adipo-8 (tAdi-8) overhang in the PCR amplicon displays anti-obesity targeting activity, while the baicalin loaded in the bcaND by embedding the amplicon plays a three-fold role as a lipid-lowering factor, bcaND size compressor, and uncoupling protein-1 (UCP1)-raised thermogenic activator. The ingenious bcaND represents an advanced multifunctional nanomaterial capable of adjusting the morphology at an optimal 400/1 molar ratio of Mg2+ to phosphate groups, compressing the size from 2.699 µm to 214.76 nm using 1 mg/mL baicalin at a temperature of 70 °C, an effective payload with amplicons of up to 98.94%, and a maximum baicalin load of 86.21 g/g DNA. Responsive release in acidic conditions (pH 5.0) occurs within 72 h, accelerating thermogenesis via UCP1 up-regulation by 2.5-fold in 3T3-L1-preadipocytes and 13.7-fold in the white-adipose-tissue (WAT) of mice, targeting adipocytes and visceral white adipose tissue. It plays an efficient synergistic role in obesity therapy in vitro and in vivo, providing a new direction for DNA self-assembly nanotechnology.

Portable dual-aptamer microfluidic chip biosensor for Bacillus cereus based on aptamer tailoring and dumbbell-shaped probes.

As food-borne pathogens, Bacillus cereus not only produce toxins that contaminate food and threaten human health, but also rely on spores to resist extreme environments. At present, the detection of B. cereus is still at the genome level and it is not easily distinguished from other Bacilli of the same group. Herein, we obtained the aptamers of B. cereus in different phases through Cell-SELEX technology. Then, through step-by-step tailoring and molecular docking, the two best performing aptamers were ascertained and the interaction revealed between the repeated G bases in the aptamer and the polar amino acids in the α-helix of the epiprotein. Based on these aptamers, a multifunctional dumbbell-shaped probe and an ultrasensitive microfluidic chip biosensor were designed. Tests showed that the novel sensor is able to complete detection within 1 h with a limit of detection (LOD) of 9.27 CFU/mL. Moreover, the sensor can be used in complex food environments, such as milk and rice, is able to detect both vegetative cells and spores, and it can also distinguish B. thuringiensis from the same flora. This study can provide a reference for the future development of food-borne pathogenic bacteria aptamer selecting, target interaction analysis, detection methods and equipment.

Tumor microenvironment-regulating nanomedicine design to fight multi-drug resistant tumors.

The tumor microenvironment (TME) is a very cunning system that enables tumor cells to escape death post-traditional antitumor treatments through the comprehensive effect of different factors, thereby leading to drug resistance. Deep insights into TME characteristics and tumor resistance encourage the construction of nanomedicines that can remodel the TME against drug resistance. Tremendous interest in combining TME-regulation measurement with traditional tumor treatment to fight multidrug-resistant tumors has been inspired by the increasing understanding of the role of TME reconstruction in improving the antitumor efficiency of drug-resistant tumor therapy. This review focuses on the underlying relationships between specific TME characteristics (such as hypoxia, acidity, immunity, microorganisms, and metabolism) and drug resistance in tumor treatments. The exciting antitumor activities strengthened by TME regulation are also discussed in-depth, providing solutions from the perspective of nanomedicine design. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

PCR Mediated Nucleic Acid Molecular Recognition Technology for Detection of Viable and Dead Foodborne Pathogens.

Living foodborne pathogens pose a serious threat to public and population health. To ensure food safety, it is necessary to complete the detection of viable bacteria in a short time (several hours to 1 day). However, the traditional methods by bacterial culture, as the gold standard, are cumbersome and time-consuming. To break through the resultant research bottleneck, PCR mediated nucleic acid molecular recognition technologies, including RNA-based reverse transcriptase PCR (RT-PCR) and DNA-based viability PCR (vPCR) have been developed in recent years. They not only sensitively amplify detection signals and quickly report detection results, but also distinguish viable and dead bacteria. Therefore, this review introduces these PCR-mediated techniques independent of culture for viable and dead foodborne pathogen detection from the nucleic acid molecular recognition principal level and describes their whole-process applications in food quality supervision, which provides a useful reference for the development of detection of foodborne pathogens in the future.

Sandwich capture ultrasensitive sensor based on biohybrid interface for the detection of Cronobacter sakazakii.

A simple, rapid and ultrasensitive visual sensing method for the detection of Cronobacter sakazakii (C. sakazakii) based on a biohybrid interface was established. During the entire sensing process, quadruple-cascade amplification showed its superior sensing performance. First, the prepared immunomagnetic beads (IMB) were used to isolate and enrich specific targets from the food matrix. After adding the fusion aptamer, the aptamer sequence specifically recognized the target and formed the immune sandwich structure of antibody-target-fusion aptamer. In addition, the fusion aptamer also included the template sequence of exponential amplification reaction (EXPAR), which contained the antisense sequence of the G-rich sequence. Therefore, a large number of G-rich sequences can be generated after EXPAR can be triggered in the presence of Bst. DNA polymerase, nicking endonuclease, cDNA, and dNTP. They were self-assembled into G-quadruplex structures and then combined with hemin to form G4/hemin DNAzyme, resulting in visible coloration and measuring absorbance at 450 nm for quantitative detection. The assay showed a limit of detection (LOD) of 2 CFU/mL in pure culture and 12 CFU/g in milk powder in optimal conditions. This method provides a promising strategy for rapid and point-of-care testing (POCT) since it does not require DNA extraction, medium culturing, and expensive instrumentation. KEY POINTS: •Single-cell level detection of C. sakazakii with ultrasensitive and rapidness •The fusion aptamer integrated recognition and amplification •Sensing analysis of C. sakazakii based on cascade amplification of biohybrid interface.