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Abstract The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.

Abstract Multifunctional biomaterial inks are in high demand for adapting hydrogels in biomedical applications through three‐dimensional (3D) printing. Our previously developed xeno‐free system consisting of anionic cellulose nanofibers (T‐CNF) and methacrylated galactoglucomannan (GGMMA) as a photo(bio)polymer provides high‐performance ink fidelity in extrusion‐based 3D printing. The fusion between nanoparticles and this biomaterial‐ink system is a promising yet challenging avenue worth exploring, due to the colloidal stability of T‐CNF being sensitive to electrostatic interactions. Mesoporous silica nanoparticles (MSNs), with their robust ceramic matrix and fine‐tunable surface chemistries, are well‐established nanocarriers for different biologicals. Here, we fabricated MSNs with different surface modifications resulting in a net surface charge ranging from highly negative to highly positive to develop printable MSNs‐laden nanocomposite biomaterial inks. We utilized rheology as a comprehensive tool to address the matrix interactions with differently surface‐charged MSNs. Fluorescently labeled bovine serum albumin (FITC‐BSA) was used as a model protein for MSN loading, whereby negatively or neutral‐charged MSNs were found suitable to formulate FITC‐BSA‐loaded biomaterial inks of T‐CNF/GGMMA. Depending on the particles’ surface charge, FITC‐BSA showed different release profiles and preserved its stability after release. Lastly, the proof‐of‐concept to deliver large‐sized biological cargo with MSN‐laden nanocomposite biomaterial inks was established via the 3D printing technique.

Objective: To investigate the renoprotective effects of luteolin on diabetes in rats. Methods: One week after administration of streptozotocin 55 mg/kg intraperitoneally, rats were given 25, 50, and 75 mg/kg/day of luteolin orally for another eight weeks. At the end of the experiment, body weight, blood glucose level, biochemical parameters for renal function (serum creatinine, blood urea nitrogen, uric acid, serum albumin, and total protein), kidney histology, matrix metalloproteinase (MMP)-2, MMP-9, and histone deacetylase 2 (HDAC-2) expression, and malondialdehyde, myeloperoxidase, and hydroxyproline content in renal tissue were evaluated. High glucose-induced damage using NRK-52E cell line was studied to evaluate cell viability and metalloenzyme expression. Additionally, in silico studies including docking and molecular dynamics simulations were conducted. Results: MMP-2, MMP-9, and HDAC-2 expressions were significantly increased in high glucose-induced NRK-52E cells and the renal tissue of diabetic rats. However, these changes were reversed by luteolin at the administered doses. Additionally, luteolin significantly reduced oxidative stress, inflammation, and fibrosis, as well as improved biochemical parameters in diabetic rats. Furthermore, luteolin at the examined doses markedly alleviated diabetes-induced histopathological changes in renal tissues. Conclusions: Luteolin effectively attenuates streptozotocin-induced diabetic nephropathy in rats by inhibiting MMP-2, MMP-9, and HDAC-2 expression, and reducing oxidative stress and inflammation.

Abstract Zeta potential is an essential surface parameter in the characterization of nanoparticles, determined at the interface of loosely bound ions (diffuse layer) at the nanoparticle surface and free ions in solution. The ionic concentration and pH of the solution are known to, by definition, influence the composition of the diffuse layer and zeta potential accordingly. Thus, to fix the solution's pH for valid zeta potential measurements, buffers are frequently used. However, an issue that remains largely neglected is that buffers could also additionally alter the electrokinetic properties of nanoparticles through specific molecular interactions. Therefore, a thorough molecular understanding of buffer–nanoparticle interactions is needed to correctly implement zeta potential results. Thus, in order to study nanoparticle–buffer interactions, we first adopted a simple experimental approach of measuring zeta potential of common polymeric nanoparticle systems at different buffer concentrations, pH, and nanoparticle–buffer fraction ratios. We observed that zwitterionic/cationic buffer molecules impart significant interference to the electrokinetic properties of structurally diverse polymer nanoparticles, by causing zeta potential suppression or even inversion during the experiments. In parallel, advancement in computation resources nowadays allow studying intermolecular interactions of nanoparticles and other complex molecules by molecular dynamics (MD) simulations. Thus, by performing MD simulations for six different polymeric nanomaterials with commonly used buffer molecules, we found that noncovalent interactions play a significant role in altering the observed zeta potential values, which may contribute to erroneous results and false particle characterizations if not taken properly into account in zeta potential measurements.

Oligonucleotide-based therapy has experienced remarkable development in the past 2 decades, but its broad applications are severely hampered by delivery vectors. Widely used viral vectors and lipid nanovectors are suffering from immune clearance after repeating usage or requiring refrigerated transportation and storage, respectively. In this work, amino-modified virus-mimetic spike silica nanoparticles (NH2-SSNs) were fabricated using a 1-pot surfactant-free approach with controlled spike lengths, which were demonstrated with excellent delivery performance and biosafety in nearly all cell types and mice. It indicated that NH2-SSNs entered cells by spike-dependent cell membrane docking and dynamin-dependent endocytosis. The positively charged spikes with proper length on the surface can facilitate the efficient encapsulation of RNAs, protect the loaded RNAs from degradation, and trigger an early endosome escape during intracellular trafficking, similarly to the cellular internalization mechanism of virions. Regarding the fantastic properties of NH2-SSNs in nucleic acid delivery, it revealed that nanoparticles with solid spikes on the surface would be excellent vehicles for gene therapy, presenting self-evident advantages in storage, transportation, modification, and quality control in large-scale production compared to lipid nanovectors.

Nanoemulsions are a rapidly growing drug delivery technology capable of increasing a drug's aqueous solubility and stability. A novel oil‐in‐water nanoemulsion using a polymer, poly(decalactone) (PDL), instead of a conventional oil was recently reported. The amount of drug loading in a polymer‐based formulation is mainly governed by the drug's solubility in the polymer. Thus, herein the power of molecular dynamics simulations (MDS) for the calculation of the Hildebrand solubility parameter to predict PDL–drug miscibility is utilized. The MDS results are subsequently verified by formulating a PDL nanoemulsion with a dispersed droplet size of less than 200 nm by using a block copolymer of PDL (mPEG‐b‐PDL) as a surfactant, with seven different hydrophobic drug molecules. The MDS results are consistent with the experimental findings in terms of increment in the aqueous solubilities of the drugs in PDL nanoemulsion, where celecoxib demonstrated the highest while methotrexate exhibited the lowest solubility increment. Consequently, the reported MDS method can be utilized to predict a drug's solubility/miscibility in PDL to estimate the level of drug loading. The MDS facilitated screening of drugs could consequently emerge as an efficient approach in designing PDL nanoemulsions stabilized by mPEG‐b‐PDL or other similar systems.

The ongoing pandemic caused by SARS-CoV-2 has gone through various phases. Since the initial outbreak, the virus has mutated several times, with some lineages showing even stronger infectivity and faster spread than the original virus. Among all the variants, omicron is currently classified as a variant of concern (VOC) by the World Health Organization, as the previously circulating variants have been replaced by it. In this work, we have focused on the mutations observed in omicron sub lineages BA.1, BA.2, BA.4 and BA.5, particularly at the receptor-binding domain (RBD) of the spike protein that is responsible for the interactions with the host ACE2 receptor and binding of antibodies. Studying such mutations is particularly important for understanding the viral infectivity, spread of the disease and for tracking the escape routes of this virus from antibodies. Molecular dynamics (MD) based alchemical free energy calculations have been shown to be very accurate in predicting the free energy change, due to a mutation that could have a deleterious or a stabilizing effect on either the protein itself or its binding affinity to another protein. Here, we investigated the significance of five spike RBD mutations on the stability of the spike protein binding to ACE2 by free energy calculations using high throughput MD simulations. For comparison, we also used conventional MD simulations combined with a Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) based approach, and compared our results with the available experimental data. Overall, the alchemical free energy calculations performed far better than the MM-GBSA approach in predicting the individual impact of the mutations. When considering the experimental variation, the alchemical free energy method was able to produce a relatively accurate prediction for N501Y, the mutant that has previously been reported to increase the binding affinity to hACE2. On the other hand, the other individual mutations seem not to have a significant effect on the spike RBD binding affinity towards hACE2.

A new series of amino acid derivatives of quinolines was synthesized through the hydrolysis of amino acid methyl esters of quinoline carboxamides with alkali hydroxide. The compounds were purified on silica gel by column chromatography and further characterized by TLC, NMR and ESI-TOF mass spectrometry. All compounds were screened for in vitro antimicrobial activity against different bacterial strains using the microdilution method. Most of the synthesized amino acid-quinolines show more potent or equipotent inhibitory action against the tested bacteria than their correspond esters. In addition, many of them exhibit fluorescent properties and could possibly be utilized as fluorophores. Molecular docking and simulation studies of the compounds at putative bacterial target enzymes suggest that the antimicrobial potency of these synthesized analogues could be due to enzyme inhibition via their favorable binding at the fluoroquinolone binding site at the GyrA subunit of DNA gyrase and/or the ParC subunit of topoisomerase-IV.