Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo.

Nucleic acid therapeutics offer tremendous promise for addressing a wide range of common public health conditions. However, the in vivo nucleic acids delivery faces significant biological challenges. Lipid nanoparticles (LNPs) possess several advantages, such as simple preparation, high stability, efficient cellular uptake, endosome escape capabilities, etc., making them suitable for delivery vectors. However, the extensive hepatic accumulation of LNPs poses a challenge for successful development of LNPs-based nucleic acid therapeutics for extrahepatic diseases. To overcome this hurdle, researchers have been focusing on modifying the surface properties of LNPs to achieve precise delivery. The review aims to provide current insights into strategies for LNPs-based organ-selective nucleic acid delivery. In addition, it delves into the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs. In conclusion, this review provides a comprehensive overview to provide guidance and valuable insights for further research and development of organ-selective nucleic acid delivery systems.

Enhanced bone regeneration by osteoinductive and angiogenic zein/whitlockite composite scaffolds loaded with levofloxacin.

Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method. Then, as a model antibiotic drug, the LEVO was loaded into zein/WH scaffolds. Moreover, the addition of WH enhanced the adhesion, differentiation, and mineralization of osteoblasts. The zein/WH/LEVO composite scaffolds not only had significant osteoinductivity but also showed excellent antibacterial properties. The prepared composite scaffolds were then implanted into a calvarial defect model to evaluate their osteogenic induction effects in vivo. Micro-CT observation and histological analysis indicate that the scaffolds can accelerate bone regeneration with the contribution of endogenous cytokines. Based on amounts of data in vitro and in vivo, the scaffolds present profound effects on improving bone regeneration, especially for the favorable osteogenic, intensive angiogenic, and alleviated inflammation abilities. The results showed that the synthesized scaffolds could be a potential material for bone tissue engineering.

Tailoring therapeutics via a systematic beneficial elements comparison between photosynthetic bacteria-derived OMVs and extruded nanovesicles.

Photosynthetic bacteria (PSB) has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties. Nevertheless, the actualization of their potential is impeded by inherent constraints, including their considerable size, heightened immunogenicity and compromised biosafety. Conquering these obstacles and pursuing more effective solutions remains a top priority. Similar to extracellular vesicles, bacterial outer membrane vesicles (OMVs) have demonstrated a great potential in biomedical applications. OMVs from PSB encapsulate a rich array of bioactive constituents, including proteins, nucleic acids, and lipids inherited from their parent cells. Consequently, they emerge as a promising and practical alternative. Unfortunately, OMVs have suffered from low yield and inconsistent particle sizes. In response, bacteria-derived nanovesicles (BNVs), created through controlled extrusion, adeptly overcome the challenges associated with OMVs. However, the differences, both in composition and subsequent biological effects, between OMVs and BNVs remain enigmatic. In a groundbreaking endeavor, our study meticulously cultivates PSB-derived OMVs and BNVs, dissecting their nuances. Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs, the latter contains a higher concentration of active ingredients and metabolites. Particularly noteworthy is the elevated levels of lysophosphatidylcholine (LPC) found in BNVs, known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization. Importantly, our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells, while also activating the EGFR/AKT/PI3K pathway. In contrast, OMVs have a pronounced aptitude in anti-cancer efforts, driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines. Thus, our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions.

Bifunctional Mo2N Nanoparticles with Nanozyme and SERS Activity: A Versatile Platform for Sensitive Detection of Biomarkers in Serum Samples.

The combined application of nanozymes and surface-enhanced Raman scattering (SERS) provides a promising approach to obtain label-free detection. However, developing nanomaterials with both highly efficient enzyme-like activity and excellent SERS sensitivity remains a huge challenge. Herein, we proposed one-step synthesis of Mo2N nanoparticles (NPs) as a "two-in-one" substrate, which exhibits both excellent peroxidase (POD)-like activity and high SERS activity. Its mimetic POD activity can catalyze the 3,3',5,5'-tetramethylbenzidine (TMB) molecule to SERS-active oxidized TMB (ox-TMB) with high efficiency. Furthermore, combining experimental profiling with theory, the mechanism of POD-like activity and SERS enhancement of Mo2N NPs was explored in depth. Benefiting from the outstanding properties of Mo2N NPs, a versatile platform for indirect SERS detection of biomarkers was developed based on the Mo2N NPs-catalyzed product ox-TMB, which acts as the SERS signal readout. The feasibility of this platform was validated using glutathione (GSH) and target antigens alpha-fetoprotein antigen (AFP) and carcinoembryonic antigen (CEA) as representatives of small molecules with a hydroxyl radical (·OH) scavenging effect and proteins with a low Raman scattering cross-section, respectively. The limits of detection of GSH, AFP, and CEA were as low as 0.1 µmol/L, 89.1, and 74.6 pg/mL, respectively. Significantly, it also showed application in human serum samples with recoveries ranging from 96.0 to 101%. The acquired values based on this platform were compared with the standard electrochemiluminescence method, and the relative error was less than ±7.3. This work not only provides a strategy for developing highly active bifunctional nanomaterials but also manifests their widespread application for multiple biomarkers analysis.

An antifouling electrochemical aptasensor based on a polydopamine-polyzwitterion copolymer for tetracycline analysis.

Matrix interference resulting from the nonspecific adsorption of non-target components, particularly proteins (fouling), onto sensor surfaces poses a persistent challenge in electrochemical detection of food hazards. The development of antifouling sensor surfaces presents a viable approach to mitigate nonspecific adsorption. In this study, a novel antifouling electrochemical aptasensor, utilizing a zwitterionic polymer, was developed for the sensitive, accurate, and selective detection of tetracycline (TC) in milk. This sensor employs a poly (dopamine)-poly (sulfobetaine methacrylate) (PDA-PSBMA) antifouling copolymer, which is synthesized through an in-situ initiated copolymerization of dopamine on the sensor's surface. Subsequently, the thiol-containing aptamers were immobilized onto the PDA-PSBMA coating through a Michael addition reaction with the poly(dopamine). The resulting antifouling electrochemical aptasensor exhibited robust antifouling performance in various single protein solutions and diluted milk samples, coupled with sensitive and selective recognition of TC. The sensor demonstrated a broad linear response range of 0.1-1000.0 ng mL-1 and a low limit of detection (LOD) of 68.0 pg mL-1. The antifouling electrochemical aptasensor proved effective in assaying TC in diluted milk, with recoveries ranging from 100.0 % to 104.4 %, eliminating the need for additional pretreatments due to its exceptional resistance to nonspecific adhesion.

Modulating the Coordination Environment of Carbon-Dot-Supported Fe Single-Atom Nanozymes for Enhanced Tumor Therapy.

Herein, carbon dot (CD)-supported Fe single-atom nanozymes with high content of pyrrolic N and ultrasmall size (ph-CDs-Fe SAzyme) are fabricated by a phenanthroline-mediated ligand-assisted strategy. Compared with phenanthroline-free nanozymes (CDs-Fe SAzyme), ph-CDs-Fe SAzyme exhibit higher peroxidase (POD)-like activity due to their structure similar to that of ferriporphyrin in natural POD. Aberration-corrected high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and X-ray absorption fine structure spectroscopy (XAFS) analyses show that metal Fe is dispersed in ph-CDs-Fe SAzyme as single atoms. Steady-state kinetic studies show that the maximum velocity (Vmax ) and turnover number (kcat ) of H2 O2  homolytic cleavage catalyzed by ph-CDs-Fe SAzyme are 3.0 and 6.2 more than those of the reaction catalyzed by CDs-Fe SAzyme. Density functional theory (DFT) calculations show that the energy barrier of the reaction catalyzed by ph-CDs-Fe SAzyme is lower than that catalyzed by CDs-Fe SAzyme. Antitumor efficacy experiments show that ph-CDs-Fe SAzyme can efficiently inhibit the growth of tumor cells both in vitro and in vivo by synergistic chemodynamic and photothermal effects. Here a new paradigm is provided for the development of efficient antitumor therapeutic approaches based on SAzyme with POD-like activity.

Research on the spatiotemporal evolution and driving mechanism of coupling coordinating between green transition of urban land use and urban land use efficiency: a case study of the Yangtze River Delta Region in China.

Analyzing the spatiotemporal characteristics and driving mechanisms of the coupling coordination between the Green Transition of Urban Land Use and urban land use efficiency can help explore the future development direction of sustainable land use in cities. This paper constructs a theoretical framework for the coupling coordination between Green Transition of Urban Land Use and urban land use efficiency. We use several models, including the super-efficiency slack-based model, the coupling coordination degree model, the non-parametric kernel density estimation method, exploratory spatial data analysis, and the geographically and temporally weighted regression model to examine the real level of Green Transition of Urban Land Use and urban land use efficiency in the Yangtze River Delta region from 2003 to 2020. Based on this, we investigate the spatiotemporal evolution characteristics and driving mechanisms of the two coupling coordination processes. The study found that (1) from 2003 to 2020, the overall trend of the coupling coordination between Green Transition of Urban Land Use and urban land use efficiency in the Yangtze River Delta region tended to be coordinated and developed, but still at a primary coordination level, with sufficient room for improvement in the future. (2) The coupling coordination level of each city in the Yangtze River Delta region from 2003 to 2020 showed obvious spatial non-equilibrium and correlation characteristics, and overall dynamic polarization effects were exhibited during the study period; the spatial pattern of high-value areas showed a regularity of prioritizing Shanghai and Zhejiang Province, gradually penetrating into Jiangsu Province and Anhui Province. (3) Economic and social factors have a positive influence on the degree of coupling coordination; natural factors and policy factors have a predominantly negative influence on the degree of coupling coordination. Research conclusions include establishing a regional collaborative development mechanism, utilizing the spatial spillover effect of leading cities; emphasizing science, education, and culture, strengthening the introduction of scientific and technological talents, increasing fiscal inputs, raising the level of economic development, and further expanding the driving effect of economic and social factors; and optimizing the layout of urban and rural construction land, developing urban land in an orderly manner, appropriately strengthening environmental regulation, thereby suppressing the negative effects caused by natural and policy factors.

Engineering an Antifouling Electrochemical Sensing Platform Based on an All-in-One Peptide and a Hierarchical ß-Bi2O3-Au Microsphere for Vancomycin Detection in Food.

Challenges associated with interference aroused by nonspecific attachment of foulants in the food matrix steered the development of sensor surfaces capable of antifouling capacity. In this study, an antifouling electrochemical sensing platform based on an all-in-one peptide (DOPA3-PPPPEKDQDKKaa) with anchoring, antifouling, and recognition functions and a hierarchical ß-Bi2O3-Au microsphere was proposed for vancomycin (Van) detection in food. The ß-Bi2O3-Au with excellent conductivity was synthesized and introduced as an electrode modifier to accelerate electron transfer on the sensor surface, enhancing sensing response. Mussel organism-inspired oligo DOPA, that is, oligo 3,4-dihydroxyphenylalanine, was employed as the anchoring segment of the all-in-one peptide, which is versatile for surfaces with different materials. PPPPEKDQDK and Kaa as antifouling and recognition segments confer abilities to resist nonspecific adsorption of foulants and specifically bind Van on the sensor surface, respectively. Notably, the excellent antifouling performance of the proposed sensor has been verified in protein solutions, carbohydrate solutions, and even in diluted milk and honey. Molecular dynamics simulation was carried out to explain the antifouling mechanism of the all-in-one peptide. The proposed sensor can detect Van sensitively and selectively with a relatively wide linear range (0.1-100 ng mL-1) and a limit of detection (LOD) as low as 0.038 ng mL-1 and support the quantification of Van in milk, milk powder, and honey samples with satisfactory recoveries within 105.3-110.8%. This antifouling electrochemical sensing platform offers a feasible strategy to reduce matrix interference, which guarantees the accurate detection of Van in food samples.

Switchable whispering gallery mode lasing via phase transition.

Combining phase-transition materials with optical microcavities may advance the applications of whispering-gallery mode (WGM) lasing in performance customization, sensing, and optical switching. In this study, switchable WGM lasing based on phase transition is reported. The device is designed by introducing the phase-transition hydrogel into the capillary microcavity. After approaching the phase-transition point in hydrogel, the number of WGM lasing modes decreases sharply with a significant blueshift in the wavelength. The phenomenon is caused by the increase in light scattering and decrease in effective refractive index of the device. Furthermore, single-mode lasing is obtained by manipulating the phase transition, which exhibits superior reversibility. This study may pave the way for designing and multifunctioning of novel WGM lasing in photonic devices.

Tunable random lasers via phase transition for information encryption.

Introducing phase transition materials to random systems provides a promising route to create new optoelectronic functionalities of random lasers. Here, a phase transition random laser with switchable lasing modes is reported, which is designed with a thermoresponsive hydrogel as scattering medium. By manipulating the phase transition in hydrogel, random lasing modes can be switched reversibility between incoherent and coherent random lasing. The phenomenon derives from the changing of light scattering properties in different phase states, thus affecting the optical feedback path of random lasing. Besides, based on its controllable and easily detectable time-domain characteristics, the phase transition random laser is applied in information encoding and transmission. It is the first time that the transition from coherent to incoherent random lasing is observed by varying the sample phase states. This work will inspire the design and application of novel random lasers in photoelectric device.

Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.

Design and fabrication of Zn@ZnO@Ag chip for Raman scattering analysis of norfloxacin in liquid milk, fish and animal feeds.

A novel and easy-to-prepare plasmonic nanoparticles doped semiconductor substrate-Zn@ZnO@Ag chip with ultra-high surface-enhanced Raman scattering (SERS) activity was fabricated for label-free, rapid and sensitive analysis of norfloxacin. The Zn@ZnO array was synthesized by surface oxidation at low temperature, followed by in-situ reduction to form leaf-like AgNPs on Zn@ZnO array without extra reducing agent, thus fabricating a Zn@ZnO@Ag chip. The ultra-high SERS activity is attributed to the synergistic effect of semiconductor characteristics of ZnO and surface plasmon resonance properties of leaf-like AgNPs. The possible enhancement mechanism was verified by density functional theory simulations. The proposed SERS method showed a wide linear range (3.0-500.0 µg/L) and low limit of detection (0.8 µg/L) for norfloxacin analysis. High sensitivity, good selectivity and acceptable recoveries (82.7-113.6%) in real sample analysis were obtained. This study offers a promising SERS chip-based platform for norfloxacin detection in the field.

Multi-walled carbon nanotubes reversing the bone formation of bone marrow stromal cells by activating M2 macrophage polarization.

Multi-walled carbon nanotubes (MWCNTs) are an excellent bone tissue repair material both in vitro and in vivo. The interactions between MWCNTs and single type of cells of bone tissue, including osteoblasts, bone marrow stromal cells (BMSCs) or osteoclasts, have been extensively studied. However, the interactions between MWCNTs with different types of cells in the bone microenvironment remain elusive. Bone microenvironment is a complex system composed of different types of cells, which have interactions between each other. In this work, the effects of MWCNTs on bone microenvironment were firstly studied by culture of MWCNTs with BMSCs, osteoblasts, osteoclasts, macrophages and vascular endothelial cells, respectively. Then, co-culture systems of macrophages-BMSCs, macrophages-calvaria and macrophages-BMSCs-vascular endothelial cells were treated with MWCNTs, respectively. The osteogenic differentiation of BMSCs and osteoblasts was inhibited when these two types of cells were cultured with MWCNTs, respectively. Strikingly, when co-culture MWCNTs with BMSCs and macrophages, the osteogenesis of BMSCs was promoted by inducing the M2 polymerization of macrophages. Meanwhile, MWCNTs promoted the bone formation in the osteolysis model of calvaria ex vivo. In addition, the formation of osteoclasts was inhibited, and angiogenesis was increased when treated with MWCNTs. This study revealed the inconsistent effects of MWCNTs on single type of bone cells and on the bone microenvironment. The results provided basic research data for the application of MWCNTs in bone tissue repair.

Adhesive, antibacterial and double crosslinked carboxylated polyvinyl alcohol/chitosan hydrogel to enhance dynamic skin wound healing.

An available dressing material which promotes skin tissue repair is of significant importance for public health. Moreover, dynamic wounds have special requirements for hydrogel dressings due to their motion state. Correspondingly, a double crosslinked hydrogel was prepared based on amide and coordination bonds from carboxylated polyvinyl alcohol (PC) and chitosan (CS)/Fe3+. The hydrogel exhibited excellent swelling ratio and suitable biodegradability, which is beneficial to the tissue repair. The results showed that hydrogels with crosslinked structure possessed better unique properties, such as stronger mechanical (78 kPa of G') and adhesion properties, and shorter self-healing time (5 mins), the change of which was consistent with dynamic wounds. The hydrogel exhibited not only antibacterial activity (98 % fatality rate), but also superior hemostatic capacity during the wound healing process. In addition, the hydrogel could shorten skin healing time to 14 days, and obviously accelerated skin structure reconstruction by promoting angiogenesis and collagen deposition. Therefore, double crosslinked hydrogel is a promising dynamic wound dressing.

A method for quantifying hepatic and intestinal ceramides on mice by UPLC-MS/MS.

BACKGROUND: Ceramide is one type of sphingolipids, is associated with the occurrence of metabolic diseases, including obesity, diabetes, cardiovascular disease, cancer, and nonalcoholic fatty liver disease. Dihydroceramide, the direct precursors of ceramide, which is converted to ceramide with the dihydroceramide desaturase, is recently regarded as involving in various biological processes and metabolic diseases. The liver and gut ceramide levels are interactional in pathophysiological condition, quantifying hepatic and intestinal ceramide levels become indispensable. The aim of this study is to establish a rapid method for the determination of ceramides including dihydroceramides in liver and small intestinal tissues for researching the mechanisms of ceramide related diseases. METHODS: The levels of Cer d18:1/2:0, Cer d18:1/6:0, Cer d18:1/12:0, Cer d18:1/14:0, Cer d18:1/16:0, Cer d18:1/17:0, Cer d18:1/18:0, Cer d18:1/20:0, Cer d18:1/22:0, Cer d18:1/24:1, Cer d18:1/24:0, dHCer d18:0/12:0, dHCer d18:0/14:0, dHCer d18:0/16:0, dHCer d18:0/18:0, dHCer d18:0/24:1 and dHCer d18:0/24:0 in mice liver and small intestine were directly quantified by ultra-high performance liquid chromatography-tandem mass spectrometry after methanol extraction. In detail, liver or small intestine tissues were thoroughly homogenized with methanol. The resultant ceramides were separated on a Waters BEH C18 column using gradient elution within 10 min. Positive electrospray ionization with multiple reaction monitoring was applied to detect. In the end, the levels of ceramides in mice liver and small intestine tissues were quantified by this developed method. RESULTS: The limits of detection and quantification of 11 ceramides and 6 dihydroceramides were 0.01-0.5 ng/mL and 0.02-1 ng/mL, respectively, and all detected ceramides had good linearities (R2 > 0.997). The extraction recoveries of ceramides at three levels were within 82.32%-115.24% in the liver and within 83.21%-118.70% in the small intestine. The relative standard deviations of intra- and inter-day precision were all within 15%. The extracting solutions of the liver and small intestine could be stably stored in the autosampler 24 h at 10 °C, the lyophilized liver and small intestine for ceramides quantification could be stably stored at least 1 week at -80 °C. The ceramides and dihydroceramides in normal mice liver and small intestinal tissues analyzed by the developed method indicated that the detected 9 ceramide and 5 dihydroceramides levels were significantly different, in which Cer d18:1/16:0, Cer d18:1/22:0, Cer d18:1/24:1, Cer d18:1/24:0 and dHCer d18:0/24:1 are the main components in the liver, whereas Cer d18:1/16:0 and dHCer d18:0/16:0 accounts for the majority of proportion in the intestinal tissues. CONCLUSION: A simple and rapid method for the quantification of 11 ceramides and 6 dihydroceramides in the animal tissues was developed and applied. The compositions of ceramides in two tissues suggested that the compositional features should to be considered when exploring the biomarkers or molecular mechanisms.

Fabrication of hierarchical ß-Bi2O3/AuAg microspheres for sensitive, selective and rapid detection of environment pollutants by surface-enhanced Raman spectroscopy.

In this paper, we report a novel surface-enhanced Raman spectroscopy (SERS) substrate based on hierarchical ß-Bi2O3/Au2Ag2 microspheres for rapid, sensitive and selective detection of environment pollutants including o-dianisidine (o-diASD) and Hg2+ in environmental samples. The sheet-like ß-Bi2O3 not only provides large specific surface areas for adsorption of molecules and AuAg, but also emerges as semiconductor matrix with chemical enhancement combined with AuAg with electromagnetic enhancement, making promising SERS activity. Particularly, the ß-Bi2O3/Au2Ag2 shows high SERS performance for 4-mercaptobenzoic acid and TMB with minimum detectable concentration of 0.1 µg/L with enhancement factor of 3.1 × 107 and 6.3 × 107, respectively. The density functional theory simulations were further adopted to explain the high SERS activity and selectivity for o-diASD and TMB. Finally, the ß-Bi2O3/Au2Ag2 was applied to direct detection of o-diASD, and indirect detection of Hg2+ by TMB marking in environmental samples. The linearity range of 0.5-200.0 and 0.2-500.0 µg/L with limit of detection of 0.2 and 0.07 µg/L for o-diASD and Hg2+ ions can be achieved, respectively. This method provides a novel strategy in designing and fabricating SERS substrates with high performance for rapid, sensitive and accurate analysis of environmental pollutants.

The Yin and Yang of the protein corona on the delivery journey of nanoparticles.

Nanoparticles-based drug delivery systems have attracted significant attention in biomedical fields because they can deliver loaded cargoes to the target site in a controlled manner. However, tremendous challenges must still be overcome to reach the expected targeting and therapeutic efficacy in vivo. These challenges mainly arise because the interaction between nanoparticles and biological systems is complex and dynamic and is influenced by the physicochemical properties of the nanoparticles and the heterogeneity of biological systems. Importantly, once the nanoparticles are injected into the blood, a protein corona will inevitably form on the surface. The protein corona creates a new biological identity which plays a vital role in mediating the bio-nano interaction and determining the ultimate results. Thus, it is essential to understand how the protein corona affects the delivery journey of nanoparticles in vivo and what we can do to exploit the protein corona for better delivery efficiency. In this review, we first summarize the fundamental impact of the protein corona on the delivery journey of nanoparticles. Next, we emphasize the strategies that have been developed for tailoring and exploiting the protein corona to improve the transportation behavior of nanoparticles in vivo. Finally, we highlight what we need to do as a next step towards better understanding and exploitation of the protein corona. We hope these insights into the "Yin and Yang" effect of the protein corona will have profound implications for understanding the role of the protein corona in a wide range of nanoparticles.