Immunogenicity-masking delivery of uricase against hyperuricemia and gout.

Improving the activity of uricase and lowering its immunogenicity remain significant challenges in the enzyme replacement management of hyperuricemia and related inflammatory diseases. Herein, an immunogenicity-masking strategy based on engineered red blood cells (RBCs) was developed for effective uricase delivery against both hyperuricemia and gout. The dynamic membrane of RBCs enabled high resistance to protease inactivation and hydrogen peroxide accumulation. Benefiting from these advantages, a single infusion of RBC-loaded uricase (Uri@RBC) performed prolonged blood circulation and sustained hyperuricemia management. Importantly, RBCs masked the immunogenicity of uricase, leading to the maintenance of UA-lowering performance after repeated infusion through reduced antibody-mediated macrophage clearance. In an acute gout model, Uri@RBC profoundly alleviated joint edema and inflammation with minimal systemic toxicity. This study supports the employment of immunogenicity-masking tools for efficient and safe enzyme delivery, and this strategy may be leveraged to improve the usefulness of enzyme replacement therapies for managing a wide range of inflammatory diseases.

Chirality Transfer of Glycopeptide across Scales Defined by the Continuity of Hydrogen Bonds.

In nature, chirality transfer refines biomolecules across all size scales, bestowing them with a myriad of sophisticated functions. Despite recent advances in replicating chirality transfer with biotic or abiotic building blocks, a molecular understanding of the underlying mechanism of chirality transfer remains a daunting challenge. In this paper, the coassembly of two types of glycopeptide molecules differing in capability of forming intermolecular hydrogen bonds enabled the involvement of discontinuous hydrogen bond, which allowed for a nanoscale chirality transfer from glycopeptide molecules to chiral micelles, yet inhibited the micrometer scale chirality transfer toward helix formation, leading to an achiral transfer from chiral micelles to planar monolayer. Upon stacking the monolayer into a bilayer, the nonsuperimposable front and back faces of the chiral micelles involved in the monolayer ribbons lead to the opposite rotation of two layers toward increasing the continuity of H-bonds. The resultant continuity triggered the symmetry breaking of stacked bilayers and thus reactivated the micrometer-scale chirality transfer toward the final helix. This work delineates a promising step toward a better understanding and replicating the naturally occurring chirality transfer events and will be instructive to future chiral material design.

Utilizing Machine Learning Models for Predicting Diamagnetic Susceptibility of Organic Compounds.

This research is centered on examining the magnetic characteristics of organic molecules, with a particular emphasis on magnetic susceptibility, an essential physical property that provides insights into molecular microstructures and reaction processes. Traditional approaches for determining and calculating magnetic susceptibility are generally inefficient and demanding. To overcome these challenges, we have introduced a novel approach using quantitative structure-property relationships, which efficiently elucidates the relationship between the structural properties of molecules and their molar magnetic susceptibility. In our study, we utilized a comprehensive database comprising molar magnetic susceptibility data for 382 organic molecules. We applied six distinct molecular fingerprinting methods-RDKit Fingerprint, Morgan Fingerprint, MACCS Keys, atom pair fingerprint, Avalon Fingerprint, and topology fingerprint-as feature inputs for training seven different machine learning models, namely random forest, AdaBoost, gradient boosting, extra trees, elastic net, support vector machine, and multilayer perceptron (MLP). Our findings revealed that the integration of the atom pair fingerprint with the MLP model yielded R2 values of 0.88 and 0.90 in the validation and test sets, respectively, showcasing exceptional predictive accuracy. This advancement significantly expedites research and development processes related to the magnetic properties of organic molecules. Moreover, by employing this effective predictive method, it is expected to considerably reduce both experimental and computational expenses while maintaining high accuracy. This development represents a breakthrough in the rapid screening and prediction of properties for various compounds, offering a new and efficient pathway in this field of study.

Hepatic-Accumulated Obeticholic Acid and Atorvastatin Self-Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic-Associated Fatty Liver Disease.

Exploration of medicines for efficient and safe management of metabolic-associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), a selective farnesoid X receptor agonist, has been reported to ameliorate injury and inflammation in various liver diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, and potential side effects. Herein a hepatic-targeted nanodrugs composed of OCA and cholesterol-lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content for orally combined treatment of MAFLD is created. Such carrier-free nanocrystals (OCAHTs) are self-assembled, not only improving the stability in gastroenteric environments but also achieving hepatic accumulation through the bile acid transporter-mediated enterohepatic recycling process. Orally administrated OCAHT outperforms the simple combination of OCA and AHT in ameliorating of liver damage and inflammation in both acetaminophen-challenged mice and high-fat diet-induced MAFLD mice with less systematic toxicity. Importantly, OCAHT exerts profoundly reverse effects on MAFLD-associated molecular pathways, including impairing lipid metabolism, reducing inflammation, and enhancing the antioxidation response. This work not only provides a facile bile acid transporter-based strategy for hepatic-targeting drug delivery but also presents an efficient and safe full-API nanocrystal with which to facilitate the practical translation of nanomedicines against MAFLD.

Large-Area Flexible Perovskite Light-Emitting Diodes Enabled by Inkjet Printing.

Metal halide perovskite light-emitting diodes (PeLEDs) are attracting increasing attention due to their potential applications in flat panel lighting and displays. The solution process, large-area fabrication, and flexibility are attractive properties of PeLEDs over traditional inorganic LEDs. However, it is still very challenging to deposit uniform perovskite films on flexible substrates using a blade or slot-die coating, as the flexible substrate is not perfectly flat. Here, the inkjet printing technique is adopted, and the key challenges are overcome step-by-step in preparing large-area films on flexible substrates. Double-hole transporting layers are first used and a wetting interfacial layer to improve the surface wettability so that the printed perovskite droplets can form a continuous wet film. The fluidic and evaporation dynamics of the perovskite wet layer is manipulated to suppress the coffee ring effect by solvent engineering. Uniform perovskite films are obtained finally on flexible substrates with different perovskite compositions. The peak external quantum efficiency of the inkjet-printed PeLEDs reaches 14.3%. Large-area flexible PeLEDs (4 × 7 cm2 ) also show very uniform emission. This work represents a significant step toward real applications of large-area PeLEDs in flexible flat-panel lighting.

Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease.

RNA interference (RNAi) presents great potential against intractable liver diseases. However, the establishment of specific, efficient, and safe delivery systems targeting hepatocytes remains a great challenge. Herein, we described a promising hepatocytes-targeting system through integrating triantennary N-acetylgalactosamine (GalNAc)-engineered cell membrane with biodegradable mesoporous silica nanoparticles, which efficiently and safely delivered siRNA to hepatocytes and silenced the target PCSK9 gene expression for the treatment of non-alcoholic fatty liver disease. Having optimized the GalNAc-engineering strategy, insertion orders, and cell membrane source, we obtained the best-performing GalNAc-formulations allowing strong hepatocyte-specific internalization with reduced Kupffer cell capture, resulting in robust gene silencing and less hepatotoxicity when compared with cationic lipid-based GalNAc-formulations. Consequently, a durable reduction of lipid accumulation and damage was achieved by systemic administering siRNAs targeting PCSK9 in high-fat diet-fed mice, accompanied by displaying desirable safety profiles. Taken together, this GalNAc-engineering biomimetics represented versatile, efficient, and safe carriers for the development of hepatocyte-specific gene therapeutics, and prevention of metabolic diseases. STATEMENT OF SIGNIFICANCE: Compared to MSN@LP-GN3 (MC3-LNP), MSN@CM-GN3 exhibited strong hepatocyte targeting and Kupffer cell escaping, as well as good biocompatibility for safe and efficient siRNA delivery. Furthermore, siPCSK9 delivered by MSN@CM-GN3 reduced both serum and liver LDL-C, TG, TC levels and lipid droplets in HFD-induced mice, resulting in better performance than MSN/siPCSK9@LP-GN3 in terms of lipid-lowering effect and safety profiles. These findings indicated promising advantages of our biomimetic GN3-based systems for hepatocyte-specific gene delivery in chronic liver diseases. Our work addressed the challenges associated with the lower targeting efficiency of cell membrane-mimetic drug delivery systems and the immunogenicity of traditional GalNAc delivery systems. In conclusion, this study provided an effective and versatile approach for efficient and safe gene editing using ligand-integrated biomimetic nanoplatforms.

Cationic mesoporous silica nanoparticles alleviate osteoarthritis by targeting multiple inflammatory mediators.

Osteoarthritis (OA) is a common and complex inflammatory disorder that is frequently compounded by cartilage degradation, synovial inflammation, and osteophyte formation. Damaged chondrocytes release multiple danger mediators that exacerbate synovial inflammation and accelerate the progression to OA. Conventional treatments targeting only a single mediator of OA have failed to achieve a strong therapeutic effect. Addressing the crucial role of multiple danger mediators in OA progression, we prepared polyethylenimine (PEI)-functionalized diselenide-bridged mesoporous silica nanoparticles (MSN-PEI) with cell-free DNA (cfDNA)-binding and anti-oxidative properties. In models of surgery-induced and collagenase-induced arthritis, we showed that these cationic nanoparticles attenuated cartilage degradation and provided strong chondroprotection against joint damage. Mechanistically, multiple target blockades alleviated oxidative stress and dampened cfDNA-induced inflammation by suppressing the M1 polarization of macrophages. This study suggests a beneficial direction for targeting multiple danger mediators in the treatment of intractable arthritis.

Oxygen-Coordinated Single Mn Sites for Efficient Electrocatalytic Nitrate Reduction to Ammonia.

Electrocatalytic nitrate reduction reaction has attracted increasing attention due to its goal of low carbon emission and environmental protection. Here, we report an efficient NitRR catalyst composed of single Mn sites with atomically dispersed oxygen (O) coordination on bacterial cellulose-converted graphitic carbon (Mn-O-C). Evidence of the atomically dispersed Mn-(O-C2)4 moieties embedding in the exposed basal plane of carbon surface is confirmed by X-ray absorption spectroscopy. As a result, the as-synthesized Mn-O-C catalyst exhibits superior NitRR activity with an NH3 yield rate (RNH3) of 1476.9 ± 62.6 µg h-1 cm-2 at - 0.7 V (vs. reversible hydrogen electrode, RHE) and a faradaic efficiency (FE) of 89.0 ± 3.8% at - 0.5 V (vs. RHE) under ambient conditions. Further, when evaluated with a practical flow cell, Mn-O-C shows a high RNH3 of 3706.7 ± 552.0 µg h-1 cm-2 at a current density of 100 mA cm-2, 2.5 times of that in the H cell. The in situ FT-IR and Raman spectroscopic studies combined with theoretical calculations indicate that the Mn-(O-C2)4 sites not only effectively inhibit the competitive hydrogen evolution reaction, but also greatly promote the adsorption and activation of nitrate (NO3-), thus boosting both the FE and selectivity of NH3 over Mn-(O-C2)4 sites.

Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

Circulating Cell-Free DNAs as a Biomarker and Therapeutic Target for Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP-induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell-free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N-acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI.

Electrochemical ammonia synthesis by reduction of nitrate on Au doped Cu nanowires.

Electrochemical nitrate reduction reaction (NO3 -RR) to synthesize valuable ammonia (NH3) is considered as a green and appealing alternative to enable an artificial nitrogen cycle. However, as there are other NO3 -RR pathways present, selectively guiding the reaction pathway towards NH3 is currently challenged by the lack of efficient catalyst. Here, we demonstrate a novel electrocatalyst for NO3 -RR consisting of Au doped Cu nanowires on a copper foam (CF) electrode (Au-Cu NWs/CF), which delivers a remarkable NH3 yield rate of 5336.0 ± 159.2 µg h-1 cm-2 and an exceptional faradaic efficiency (FE) of 84.1 ± 1.0% at -1.05 V (vs. RHE). The 15N isotopic labelling experiments confirm that the yielded NH3 is indeed from the Au-Cu NWs/CF catalyzed NO3 -RR process. The XPS analysis and in situ infrared spectroscopy (IR) spectroscopy characterization results indicated that the electron transfer between the Cu and Au interface and oxygen vacancy synergistically decreased the reduction reaction barrier and inhibited the generation of hydrogen in the competitive reaction, resulting in a high conversion, selectivity and FE for NO3 -RR. This work not only develops a powerful strategy for the rational design of robust and efficient catalysts by defect engineering, but also provides new insights for selective nitrate electroreduction to NH3.

Probiotic-Inspired Nanomedicine Restores Intestinal Homeostasis in Colitis by Regulating Redox Balance, Immune Responses, and the Gut Microbiome.

Microbiota-based therapeutics offer innovative strategies to treat inflammatory bowel diseases (IBDs). However, the poor clinical outcome so far and the limited flexibility of the bacterial approach call for improvement. Inspired by the health benefits of probiotics in alleviating symptoms of bowel diseases, bioartificial probiotics are designed to restore the intestinal microenvironment in colitis by regulating redox balance, immune responses, and the gut microbiome. The bioartificial probiotic comprises two components: an E. coli Nissle 1917-derived membrane (EM) as the surface and the biodegradable diselenide-bridged mesoporous silica nanoparticles (SeM) as the core. When orally administered, the probiotic-inspired nanomedicine (SeM@EM) adheres strongly to the mucus layer and restored intestinal redox balance and immune regulation homeostasis in a murine model of acute colitis induced by dextran sodium sulfate. In addition, the respective properties of the EM and SeM synergistically alter the gut microbiome to a favorable state by increasing the bacterial diversity and shifting the microbiome profile to an anti-inflammatory phenotype. This work suggests a safe and effective nanomedicine that can restore intestinal homeostasis for IBDs therapy.

A Mechanistic Study of Asymmetric Transfer Hydrogenation of Imines on a Chiral Phosphoric Acid Derived Indium Metal-Organic Framework.

A density functional theory (DFT) study is reported to examine the asymmetric transfer hydrogenation (ATH) of imines catalyzed by an indium metal-organic framework (In-MOF) derived from a chiral phosphoric acid (CPA). It is revealed that the imine and reducing agent (i.e., thiazoline) are simultaneously adsorbed on the CPA through H-bonding to form an intermediate, subsequently, a proton is transferred from thiazoline to imine. The transition state TS-R and TS-S are stabilized on the CPA via H-bonding. Compared to the TS-S, the TS-R has shorter H-bonding distances and longer C-H···π distances, it is more stable and experiences less steric hindrance. Consequently, the TS-R exhibits a lower activation barrier affording to the (R)-enantiomer within 68.1% ee in toluene. Imines with substituted groups such as -NO2, -F, and -OCH3 are used to investigate the substitution effects on the ATH. In the presence of an electron-withdrawing group like -NO2, the electrophilicity of imine is enhanced and the activation barrier is decreased. The non-covalent interactions and activation-strain model (ASM) analysis reveal that the structural distortions and the differential noncovalent interactions of TSs in a rigid In-MOF provide the inherent driving force for enantioselectivity. For -OCH3 substituted imine, the TS-S has the strongest steric hindrance, leading to the highest enantioselectivity. When the solvent is changed from toluene to dichloromethane, acetonitrile, and dimethylsulfoxide with increasing polarity, the activation energies of transition state increase whereas their difference decreases. This implies the reaction is slowed down and the enantioselectivity becomes lower in a solvent of smaller polarity. Among the four solvents, toluene turns out to be the best for the ATH. The calculated results in this study are in fairly good agreement with experimental observations. This study provides a mechanistic understanding of the reaction mechanism, as well as substitution and solvent effects on the activity and enantioselectivity of the ATH. The microscopic insights are useful for the development of new chiral MOFs toward important asymmetric reactions.

Hydrogen Peroxide Assisted Electrooxidation of Benzene to Phenol over Bifunctional Ni-(O-C2 )4 Sites.

Direct electrocatalytic oxidation of benzene has been regarded as a promising approach for achieving high-value phenol product, but remaining a huge challenge. Here an oxygen-coordinated nickel single-atom catalyst (Ni-O-C) is reported with bifunctional electrocatalytic activities toward the two-electron oxygen reduction reaction (2e- ORR) to H2 O2 and H2 O2 -assisted benzene oxidation to phenol. The Ni-(O-C2 )4 sites in Ni-O-C ar proven to be the catalytic active centers for bifunctional 2e- ORR and H2 O2 -assisted benzene oxidation processes. As a result, Ni-O-C can afford a benzene conversion as high as 96.4 ± 3.6% with a phenol selectivity of 100% and a Faradaic efficiency (FE) of 80.2 ± 3.2% with the help of H2 O2 in 0.1 m KOH electrolyte at 1.5 V (vs RHE). A proof of concept experiment with Ni-O-C concurrently as cathode and anode in a single electrochemical cell demonstrates a benzene conversion of 33.4 ± 2.2% with a phenol selectivity of 100% and a FE of 44.8 ± 3.0% at 10 mA cm-2 .

Bioactive Injectable Hydrogel Dressings for Bacteria-Infected Diabetic Wound Healing: A "Pull-Push" Approach.

Chronic diabetic wound healing remains a challenge due to the existence of excessive danger molecules and bacteria in the inflammatory microenvironment. There is an urgent need for advanced wound dressings that target both inflammation and infection. Here, a bioactive hydrogel without loading any anti-inflammatory ingredients is rationally designed to achieve a "Pull-Push" approach for efficient and safe bacteria-infected diabetic wound healing by integrating danger molecule scavenging (Pull) with antibiotic delivery (Push) in the inflammatory microenvironment. The cationic hydrogel, termed the OCMC-Tob/PEI hydrogel, is fabricated by the conjugation of polyethylenimine (PEI) and tobramycin (Tob) on an oxidized carboxymethyl cellulose (OCMC) backbone via the Schiff base reaction with injectable, self-healing, and biocompatible properties. The OCMC-Tob/PEI hydrogel not only displays the remarkable capability of capturing multiple negatively charged danger molecules (e.g., cell-free DNA, lipopolysaccharides, and tumor necrosis factor-α) to ameliorate anti-inflammation effects but also achieves controllable long-term antibacterial activity by the pH-sensitive release of Tob. Consequently, this multifunctional hydrogel greatly expedites the wound closure rate with combined anti-inflammation and anti-infection effects on Pseudomonas aeruginosa-infected diabetic wounds. Our work provides a highly versatile treatment approach for chronic diabetic wounds and a promising dressing for regenerative medicine.

Molecular dynamic simulation: Study on the recognition mechanism of linear ß-(1 → 3)-D-glucan by Dectin-1.

By combining molecular dynamic (MD) simulation and docking techniques, we systematically investigated the recognition between linear ß-(1 â†’ 3)-glucan (bglc) and Dectin-1. The binding structure exhibits apparent endo-type recognition between the C-type lectin-like domain (CTLD) groove formed by Trp221, His223, Tyr228, as well as other residues around them, and the conformational patterns of triple-helix bglc. Trp221, His223, and Tyr228 play an important role in stabilizing the recognition complex through forming a simple but fixed hydrogen bond network with the C6 and C4 hydroxyls. This recognition mode shows a clear preference on the relative direction of the triple-helix bglc with respect to the CTLD groove. Moreover, this recognition mode is not influenced by chain length, except when reaching the lower limit that may destabilize triple-helix formation. Double-helix and single-helix structures lead to unstable recognition, because they abandon the ordered packing pattern in triple-helix and present more flexible chain conformations.

A nanoparticulate dual scavenger for targeted therapy of inflammatory bowel disease.

A therapeutic strategy that targets multiple proinflammatory factors in inflammatory bowel disease (IBD) with minimal systemic side effects would be attractive. Here, we develop a drug-free, biodegradable nanomedicine that acts against IBD by scavenging proinflammatory cell-free DNA (cfDNA) and reactive oxygen species (ROS). Polyethylenimine (PEI) was conjugated to antioxidative diselenide-bridged mesoporous organosilica nanoparticles (MONs) to formulate nanoparticles (MON-PEI) that exhibited high cfDNA binding affinity and ROS-responsive degradation. In ulcerative colitis and Crohn's disease mouse colitis models, orally administered MON-PEI accumulated preferentially in the inflamed colon and attenuated colonic and peritoneal inflammation by alleviating cfDNA- and ROS-mediated inflammatory responses, allowing a reduced dose frequency and ameliorating colitis even after delayed treatment. This work suggests a new nanomedicine strategy for IBD treatment.

Analysis of Serum Metabolomics in Rats with Osteoarthritis by Mass Spectrometry.

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

Flow-driven competition between two capsules passing through a narrow pore.

By incorporating a distance function into the finite element simulation, we investigate the flow-driven competition between two soft capsules passing through a narrow pore, employing the arbitrary Lagrangian-Eulerian formulation to satisfy the boundary conditions for fluid flow and capsule deformation. In our simulations, the motion and deformation of the capsules can be described in an intuitive manner, and the order in which capsules of different sizes pass through a pore can be clearly determined. Meanwhile, when the capsules are near the narrow pore, the change of the flow field is also very interesting and can be expressed intuitively. It is shown that, driven by the Poiseuille flow, the larger capsule has a stronger tendency to pass through the pore than the small one, which can be attributed to the greater resistance and the volume advantage of the larger capsule. In addition, we demonstrate that this tendency can be reversed by changing the inlet velocity and setting the initial position of the smaller capsule closer to the axis of the pore. And as long as the large one passes through first, the small one will offset the axis to the same orientation as the initial, while the large one always moves along the axis.