Determining the Role of Surfactant on the Cytosolic Delivery of DNA Cross-Linked Micelles.

Nucleic Acid Nanocapsules (NANs) are nucleic acid nanostructures that radially display oligonucleotides on the surface of cross-linked surfactant micelles. Their chemical makeup affords the stimuli-responsive release of therapeutically active DNA-surfactant conjugates into the cells. While NANs have so far demonstrated the effective cytosolic delivery of their nucleic acid cargo, as seen indirectly by their gene regulation capabilities, there remain gaps in the molecular understanding of how this process happens.

Cellular Uptake Mechanism of Nucleic Acid Nanocapsules and Their DNA-Surfactant Building Blocks.

Nucleic acid nanocapsules (NANs) are enzyme-responsive DNA-functionalized micelles built for the controlled release of DNA-surfactant conjugates (DSCs) that present sequences with demonstrated therapeutic potential. Here, we investigate the mechanisms by which DSCs gain access to intracellular space and determine the effects of serum on the overall uptake and internalization mechanism of NANs. Using pharmacological inhibitors to selectively block certain pathways, we show, through confocal visualization of cellular distribution and flow cytometry quantification of total cellular association, that scavenger receptor-mediated, caveolae-dependent endocytosis is the major cellular uptake pathway of NANs in the presence and absence of serum.

Controlled Release of a Dual Zinc-Sensing and Gene Regulating Small Molecule from DNA Micelles.

Intracellular zinc ions are essential for various biological cell processes and are often dysregulated in many diseases de-pending on their location, protein binding affinity, and concentration in the cell. Due to their prevalence in diseases, it is important to not only effectively sense but chelate the often excess amount of zinc in a cell to alleviate further disease progression. N, N, N', N'-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN) is a selective zinc chelator but its water-insoluble nature and general cytotoxicity limit its therapeutic potential.

RNA and nanocarriers: next generation drug and delivery platform take center stage.

The unprecedented rapid deployment of mRNA vaccines against COVID-19 can be traced back to the early studies of RNA nanocarriers, including the study by Zimmermann et al. which showcased the effectiveness of RNA nanocarriers in vivo. This study, among others, ultimately resulted in Onpattro, the first FDA-approved RNA formulation.

Multi-layered stimuli responsive DNA micelles for the stepwise controlled release of small molecules.

Controllable release of multiple distinct cargoes from a nanomaterial is crucial to a variety of therapeutic and catalytic applications. In this study, we describe a DNA functionalized multi-layered surface crosslinked micelle (mlSCM) consisting of individually degradable layers. The DNA modified mlSCM has the ability to encapsulate separate small molecule cargo in distinct compartments within the nanocapsule, separated by chemical crosslinkers.

Clinical and Organizational Impacts of Medical Ordering Settings on Patient Pathway and Community Pharmacy Dispensing Process: The Prospective ORDHOSPIVILLE Study.

During the dispensing process of medical orders (MOs), community pharmacists (CPs) can manage drug-related problems (DRPs) by performing pharmacist interventions (PIs). There is little evidence that the PI rate is higher with MOs from hospitals (MOHs) than ambulatory (MOAs) settings, and their impact on the patient and community pharmacy is unknown. The primary objective of this study was to compare the MOH and MOA PI rates.

Simulation-Based Teaching of Telemedicine for Future Users of Teleconsultation and Tele-Expertise: Feasibility Study.

Background: Health care professionals worldwide are increasingly using telemedicine in their daily clinical practice. However, there is still a lack of dedicated education and training even though it is needed to improve the quality of the diverse range of telemedicine activities. Simulation-based training may be a useful tool in telemedicine education and training delivery.

A GATA3 Targeting Nucleic Acid Nanocapsule for Gene Regulation in Asthma.

Allergic asthma is one of the leading chronic lung diseases of both children and adults worldwide, resulting in significant morbidity and mortality in affected individuals. Many patients have severe asthma, which is refractory to treatment, illustrating the need for the development of new therapeutics for this disease. Herein, we describe the use of a peptide cross-linked nucleic acid nanocapsule (NAN) for the delivery of a GATA3-specific DNAzyme to immune cells, with demonstration of modulated transcriptional activity and behavior of those cells.

Viral Mimicry as a Design Template for Nucleic Acid Nanocarriers.

Therapeutic nucleic acids hold immense potential in combating undruggable, gene-based diseases owing to their high programmability and relative ease of synthesis. While the delivery of this class of therapeutics has successfully entered the clinical setting, extrahepatic targeting, endosomal escape efficiency, and subcellular localization. On the other hand, viruses serve as natural carriers of nucleic acids and have acquired a plethora of structures and mechanisms that confer remarkable transfection efficiency.

Individual versus collective debriefing after interprofessional training course simulation: The randomised DEBRIEF-SIM trial.

Introduction: Debriefing is a critical phase in simulation-based education that is extremely time-consuming for the instructors. The aim of the study was to assess whether a collective debriefing was non-inferior to an individual debriefing to improve learning outcomes after a simulation session.

Methods: This randomised controlled multicentre non-inferiority study included pairs comprising one resident and one student nurse in anaesthesia.

Tracking nucleic acid nanocapsule assembly, cellular uptake and disassembly using a novel fluorescently labeled surfactant.

Intracellular trafficking and delivery of nucleic acids is an area of growing interest, particularly as it relates to therapeutic applications. Spectroscopic methods have been used to observe and quantitatively measure the delivery of oligonucleotides both and . Herein we demonstrate the use of a new fluorophore labeled surfactant presenting a solvatochromatic chromophore for tracking the assembly and degradation of a hybrid biomaterial we refer to as a nucleic acid nanocapsule (NAN).

Controlled release of small molecules and proteins from DNA-surfactant stabilized metal organic frameworks.

This work highlights a multifunctional nanoscale material which can effectively compartmentalize small molecules and biomolecules into a single, micellar structure with programmable degradation properties resulting in highly controllable release properties. The nanomaterial consists of a ZIF-8 metal organic framework (MOF) encapsulated within a DNA surfactant micelle assembly, referred to as a nucleic acid nanocapsule (NAN). NANs have been demonstrated to enter cells through endocytosis and result in intracellular cargo release upon enzyme-triggered degradation.

Chimeric siRNA-DNA Surfactants for the Enhanced Delivery and Sustained Cytotoxicity of a Gold(III) Metallodrug.

Using a recently developed nucleic acid delivery platform, we demonstrate the effective delivery of metallodrug [AuBr(SSC-Inp-OEt)] (AP228; Inp = isonipecotic moiety), a hydrophobic, low solubility gold complex cytotoxic to cancer cells. It is shown that AP228 is delivered more effectively into HeLa cells using micellular surfactant assemblies compared to that of a more polar derivative [AuBr(SSC-Inp-GlcN1)] (AP209; GlcN1 = (α,β)-d-glucosamino moiety). When AP228 is codelivered with siRNA targeting Bcl-2, a key regulator of apoptosis, the overall cytotoxic therapeutic effects of the drug are maximized.

Polymer stiffness governs template mediated self-assembly of liposome-like nanoparticles: simulation, theory and experiment.

This study suggests that the self-assembly of a template-mediated liposome (TML) can be utilized as a general method to produce liposomes with controlled sizes. A polymer tethered core is used here as a starting configuration of a TML. Lipids anchored to the free ends of the tethered polymers direct the self-assembly of surrounding free lipid molecules to form liposome-like nanoparticles.

Towards Self-Transfecting Nucleic Acid Nanostructures for Gene Regulation.

Nanoscale structures of therapeutic nucleic acids have shown enormous potential to help clinicians realize the promise of personaliz ed medicine using gene-specific treatments. With the advent of better sequencing through bioinformatic approaches and advancements in nucleic acid stabilization chemistries, the field of synthetic nucleic acid nanomaterials has advanced tremendously. This review focuses on an emerging strategy geared at gene silencing without the use of traditional polycation-based transfection agents and discusses how such nanostructures are being chemically tailored to navigate biological systems to improve their circulation time and biodistribution.

First report of natural Wolbachia infection in the malaria mosquito Anopheles arabiensis in Tanzania.

Background: Natural infections of the endosymbiont bacteria Wolbachia have recently been discovered in populations of the malaria mosquito Anopheles gambiae (s.l.) in Burkina Faso and Mali, West Africa.

Enzymatically Ligated DNA-Surfactants: Unmasking Hydrophobically Modified DNA for Intracellular Gene Regulation.

Herein, we describe the characterization of a novel self-assembling and intracellular disassembling nanomaterial for nucleic acid delivery and targeted gene knockdown. By using a recently developed nucleic acid nanocapsule (NAN) formed from surfactants and conjugated DNAzyme (DNz) ligands, it is shown that DNz-NAN can enable cellular uptake of the DNAzyme and result in 60 % knockdown of a target gene without the use of transfection agents. The DNAzyme also exhibits activity without chemical modification, which we attribute to the underlying nanocapsule design and release of hydrophobically modified nucleic acids as a result of enzymatically triggered disassembly of the NAN.

The precipitation, growth and stability of mercury sulfide nanoparticles formed in the presence of marine dissolved organic matter.

The methylation of mercury is known to depend on the chemical forms of mercury (Hg) present in the environment and the methylating bacterial activity. In sulfidic sediments, under conditions of supersaturation with respect to metacinnabar, recent research has shown that mercury precipitates as β-HgS(s) nanoparticles (β-HgS(s)nano). Few studies have examined the precipitation of β-HgS(s)nano in the presence of marine dissolved organic matter (DOM).

Nucleic Acid Nanocapsules for Enzyme-Triggered Drug Release.

Herein we describe a nucleic acid functionalized nanocapsule in which nucleic acid ligands are assembled and disassembled in the presence of enzymes. The particles are fully degradable in response to esterases due to an embedded ester cross-linker in the particle's core. During synthesis the nanocapsules can be loaded with hydrophobic small molecules and post self-assembly undergo covalent cross-linking using copper catalyzed click chemistry.

Self-assembly of core-polyethylene glycol-lipid shell (CPLS) nanoparticles and their potential as drug delivery vehicles.

Herein a new multifunctional formulation, referred to as a core-polyethylene glycol-lipid shell (CPLS) nanoparticle, has been proposed and studied in silico via large scale coarse-grained molecular dynamics simulations. A PEGylated core with surface tethered polyethylene glycol (PEG) chains is used as the starting configuration, where the free ends of the PEG chains are covalently bonded with lipid molecules (lipid heads). A complete lipid bilayer is formed at the surface of the PEGylated particle core upon addition of free lipids, driven by the hydrophobic properties of the lipid tails, leading to the formation of a CPLS nanoparticle.

Modulating the Bond Strength of DNA-Nanoparticle Superlattices.

A method is introduced for modulating the bond strength in DNA-programmable nanoparticle (NP) superlattice crystals. This method utilizes noncovalent interactions between a family of [Ru(dipyrido[2,3-a:3',2'-c]phenazine)(N-N)2](2+)-based small molecule intercalators and DNA duplexes to postsynthetically modify DNA-NP superlattices. This dramatically increases the strength of the DNA bonds that hold the nanoparticles together, thereby making the superlattices more resistant to thermal degradation.

Ribozyme-Spherical Nucleic Acids.

Ribozymes are highly structured RNA sequences that can be tailored to recognize and cleave specific stretches of mRNA. Their current therapeutic efficacy remains low due to their large size and structural instability compared to shorter therapeutically relevant RNA such as small interfering RNA (siRNA) and microRNA (miRNA). Herein, a synthetic strategy that makes use of the spherical nucleic acid (SNA) architecture to stabilize ribozymes and transfect them into live cells is reported.

Duplex-selective ruthenium-based DNA intercalators.

We report the design and synthesis of small molecules that exhibit enhanced luminescence in the presence of duplex rather than single-stranded DNA. The local environment presented by a well-known [Ru(dipyrido[3,2-a:2',3'-c]phenazine)L2 ](2+) -based DNA intercalator was modified by functionalizing the bipyridine ligands with esters and carboxylic acids. By systematically varying the number and charge of the pendant groups, it was determined that decreasing the electrostatic interaction between the intercalator and the anionic DNA backbone reduced single-strand interactions and translated to better duplex specificity.

Biocompatible infinite-coordination-polymer nanoparticle-nucleic-acid conjugates for antisense gene regulation.

Herein, we report the synthesis of DNA-functionalized infinite-coordination-polymer (ICP) nanoparticles as biocompatible gene-regulation agents. ICP nanoparticles were synthesized from ferric nitrate and a ditopic 3-hydroxy-4-pyridinone (HOPO) ligand bearing a pendant azide. Addition of Fe(III) to a solution of the ligand produced nanoparticles, which were colloidally unstable in the presence of salts.