Lipid liquid-crystalline mesophases provide nanostructured aqueous and hydrophobic domains that can direct chemical transformations under soft confinement. Here, we investigate how monomer polarity and mesophase topology govern free-radical polymerization within inverse lipid liquid-crystalline thin films using in situ grazing-incidence small-angle neutron scattering. Deuterated glycerol monooleate / lauric acid films forming bicontinuous cubic ( Pn3m type) and inverse hexagonal ( H 2 ) mesophases were used as nanoconfined reaction platforms for acrylate monomers spanning hydrophilic, cationic, and hydrophobic character. Selective deuteration and solvent contrast variation enabled in situ investigation of structural evolution during hydration, monomer incorporation, and photopolymerization under fully hydrated conditions. The observed structural responses were consistent with the partitioning of hydrophilic monomers into aqueous domains and butyl acrylate into lipid domains prior to polymerization. Photopolymerization within Pn3m type bicontinuous cubic films triggered pronounced topology-dependent restructuring into primitive Im3m cubic phases. In contrast, H 2 mesophases showed no detectable structural changes during photopolymerization in thin films, whereas corresponding bulk systems exhibited structural evolution after polymerization. This discrepancy suggests that confinement topology, hydration geometry, and local compositional changes collectively influence confined reaction pathways and structural responses. These findings establish that polymerization-induced structural remodeling in lipid nanoreactors is governed by monomer partitioning and mesophase connectivity. The work provides mechanistic design principles for engineering confinement-directed polymerization pathways and programmable polymer–lipid hybrid nanomaterials.

Polyethylene glycol is a widely utilized polymer with diverse applications in pharmaceutical and biomedical sciences, owing to its outstanding solubility, excellent biocompatibility, and proven ability to enhance pharmacokinetic profiles. Deuterium labeling of PEG provides a powerful tool for probing drug distribution and metabolic behavior, thereby facilitating the development of advanced diagnostic and therapeutic agents. Despite the pervasive use of PEG, direct methods for its deuterium incorporation have been reported only sparingly. Herein, we report an efficient and practical protocol for the direct deuterium labeling of PEG derivatives employing a readily removable heterogeneous catalyst and inexpensive heavy water as the deuterium source. This strategy offers a cost-effective and operationally straightforward approach and is readily applicable to PEG derivatives bearing terminal, easily deprotectable MOM groups. The present methodology is expected to expand the synthetic versatility of PEG functionalization and underscores the potential of direct deuteration strategies in pharmacological and biomedical research.

Metal-catalyzed hydrothermal deuteration is a versatile approach for hydrogen-deuterium exchange (HDE) reactions, offering precise isotopic labeling of organic molecules. Here, we report the development of a scalable flow deuteration method that permits the tunable isotopic selectivity of saturated short-chain fatty acids over platinum group metal (PGM) catalysts. Benchmarking against conventional batch hydrothermal deuteration in pressurized vessels demonstrated that flow deuteration sustains high steady-state activity, improves single-pass yields, and provides mechanistic insights into isotopologue formation. Under optimized conditions, 10 wt % Pt/C achieved 93% D (deuterium incorporation) and 98% isolated yield of sodium butyrate-d(7) in 90 min time-on-stream (TOS) under H-2-free conditions (20 bar D2O, 220 degrees C) in a single pass. Notably, flow deuteration afforded high selectivity to -d(7) (60%) and -d(6) (32%) isotopologues and favored the formation of thermodynamically stable isotopologues at elevated temperatures, as confirmed by isotopologue analysis (MS) and isotopomer distribution (NMR). The intrinsic activity of Pt (TOF = 6 h(-1)) exceeds that of Pd metal (with similar loading) by an order of magnitude, determined at iso-conversion (<20% conversion under differential reactor conditions). In situ catalyst activation allowed for four consecutive reaction cycles without loss of activity, with the catalyst maintaining stability over 540 min of time-on-stream. Density functional theory calculations revealed a facile and preferential alpha-C-H activation of butyric acid via cooperative C- and O-metal interactions on Pt, effectively lowering activation barriers at other C-sites and thereby promoting perdeuteration compared to Pd. Process intensification under flow conditions resulted in a 4-fold increase in the production rate, underscoring the potential of this approach for the scalable, selective, and operationally efficient synthesis of deuterated short-chain fatty acids. This work presents a viable blueprint for platform-specific isotopic labeling using flow chemistry.

Lipid nanoparticles (LNPs) are effective carriers for messenger ribonucleic acid (mRNA) delivery in vaccines; however, their reliance on extreme cold-chain storage limits global manufacturing and distribution. Conventional LNPs are formed by rapidly mixing four lipids with mRNA through electrostatic interactions between cationic ionizable lipids and negatively charged nucleic acids, facilitating nucleation and precipitation of mRNA-loaded LNPs. However, this binding also accelerates mRNA degradation, requiring stringent cold storage which limits widespread vaccine deployment. To overcome this limitation, we introduce a post-loading strategy in which empty LNPs (eLNPs) are first fabricated and RNA is subsequently loaded at a later stage. Using scalable confined impinging jet (CIJ) mixers, we optimized pH, buffer composition, lipid concentration, and ethanol content to produce colloidally stable eLNPs. Controlled adjustment of ethanol content and pH enabled efficient incorporation of four distinct RNA payloads while maintaining loaded LNP diameters below 100 nm. Post-loaded LNPs demonstrated mRNA delivery efficiencies in HeLa cells comparable to those of conventionally co-precipitated LNPs. Consistent size distributions and zeta potentials further confirmed comparable surface properties. Structural characterization by x-ray and neutron scattering revealed similar internal architectures for post-loaded and co-precipitated LNPs without compromising RNA loading efficiency. Together, these results demonstrate equivalent cellular delivery performance between the two formulations. This post-loading approach enables decentralized assembly of mRNA LNPs at the point of administration, with both eLNPs and mRNA stored under mild refrigeration, thereby improving vaccine accessibility. Moreover, eLNPs function as modular laboratory reagents, facilitating the translation of mRNA research toward clinical applications.

Three nonhalogenated ionic liquids (ILs) dissolved in 2-ethylhexyl laurate (2-EHL), a biodegradable oil, are investigated in terms of their bulk and electro-interfacial nanoscale structures using small-angle neutron scattering (SANS) and neutron reflectivity (NR). The ILs share the same trihexyl(tetradecyl)phosphonium ([P-6,P-6,P-6,P-14](+)) cation paired with different anions, bis(mandelato)borate ([BMB](-)), bis(oxalato)borate ([BOB](-)), and bis(salicylato)borate ([BScB](-)). SANS shows a high aspect ratio tubular self-assembly structure characterized by an IL core of alternating cations and anions with a 2-EHL-rich shell or corona in the bulk, the geometry of which depends upon the anion structure and concentration. NR also reveals a solvent-rich interfacial corona layer. Their electro-responsive behavior, pertaining to the structuring and composition of the interfacial layers, is also influenced by the anion identity. [P-6,P-6,P-6,P-14][BOB] exhibits distinct electroresponsiveness to applied potentials, suggesting an ion exchange behavior from cation-dominated to anion-rich. Conversely, [P-6,P-6,P-6,P-14][BMB] and [P-6,P-6,P-6,P-14][BScB] demonstrate minimal electroresponses across all studied potentials, related to their different dissociative and diffusive behavior. A mixed system is dominated by the least soluble IL but exhibits an increase in disorder. This work reveals the subtlety of anion architecture in tuning bulk and electro-interfacial properties, offering valuable molecular insights for deploying nonhalogenated ILs as additives in biodegradable lubricants and supercapacitors.

Commercial (protiated) samples of the "green" and biodegradable bioester 2-ethylhexyl laurate (2-EHL) were mixed with D-2-EHL synthesized by hydrothermal deuteration, with the mixtures demonstrating bulk structuring in small-angle neutron scattering measurements. Analysis in a polymer scattering framework yielded a radius of gyration (R (g)) of 6.5 angstrom and a Kuhn length (alternatively described as the persistence length or average segment length) of 11.2 angstrom. Samples of 2-EHL dispersed in acetonitrile formed self-assembled structures exceeding the molecular dimensions of the 2-EHL, with a mean aggregation number (N-agg) of 3.5 +/- 0.2 molecules across the tested concentrations. We therefore present structural evidence that this ester can function as a nonionic (co)-surfactant. The available surfactant-like conformations appear to enable performance beyond the low calculated hydrophilic-lipophilic balance value of 2.9. Overall, our data offer an explanation for 2-EHL's interfacial adsorption properties via self-assembly, resulting in strong emolliency and lubricity for this sustainable ester-based bio-oil.

Peptide-based liquid droplets (coacervates) produced by spontaneous liquid-liquid phase separation (LLPS), have emerged as a promising class of drug delivery systems due to their high entrapping efficiency and the simplicity of their formulation. However, the detailed mechanisms governing their interaction with cell membranes and cellular uptake remain poorly understood. In this study, we investigated the interactions of peptide coacervates composed of HBpep—peptide derived from the histidine-rich beak proteins (HBPs) of the Humboldt squid—with model cellular membranes in the form of supported lipid bilayers (SLBs). We employed quartz crystal microbalance with dissipation monitoring (QCM-D), neutron reflectometry (NR) and atomistic molecular dynamics (MD) simulations to reveal the nature of these interactions in the absence of fluorescent labels or tags. HBpep forms small oligomers at pH 6 whereas it forms µm-sized coacervates at physiological pH. Our findings reveal that both HBpep oligomers and HBpep-coacervates adsorb onto SLBs at pH 6 and 7.4, respectively. At pH 6, when the peptide carries a net positive charge, HBpep oligomers insert into the SLB, facilitated by the peptide’s interactions with the charged lipids and cholesterol. Importantly, however, HBpep coacervate adsorption at physiological pH, when it is largely uncharged, is fully reversible, suggesting no significant lipid bilayer rearrangement. HBpep coacervates, previously identified as efficient drug delivery vehicles, do not interact with the lipid membrane in the same manner as traditional cationic drug delivery systems or cell-penetrating peptides. Based on our findings, HBpep coacervates at physiological pH cannot cross the cell membrane by a simple passive mechanism and are thus likely to adopt a non-canonical cell entry pathway.

High-density lipoproteins (HDLs) are responsible for removing cholesterol from arterial walls, through a process known as reverse cholesterol transport. The main protein in HDL, apolipoprotein A-I (ApoA-I), is essential to this process, and changes in its sequence significantly alter HDL structure and functions. ApoA-I amyloidogenic variants, associated with a particular hereditary degenerative disease, are particularly effective at facilitating cholesterol removal, thus protecting carriers from cardiovascular disease. Thus, it is conceivable that reconstituted HDL (rHDL) formulations containing ApoA-I proteins with functional/structural features similar to those of amyloidogenic variants hold potential as a promising therapeutic approach. Here we explored the effect of protein cargo and lipid composition on the function of rHDL containing one of the ApoA-I amyloidogenic variants G26R or L174S by Fourier transformed infrared spectroscopy and neutron reflectometry. Moreover, small-angle x-ray scattering uncovered the structural and functional differences between rHDL particles, which could help to comprehend higher cholesterol efflux activity and apparent lower phospholipid (PL) affinity. Our findings indicate distinct trends in lipid exchange (removal vs. deposition) capacities of various rHDL particles, with the rHDL containing the ApoA-I amyloidogenic variants showing a markedly lower ability to remove lipids from artificial membranes compared to the rHDL containing the native protein. This effect strongly depends on the level of PL unsaturation and on the particles' ultrastructure. The study highlights the importance of the protein cargo, along with lipid composition, in shaping rHDL structure, contributing to our understanding of lipid-protein interactions and their behavior.

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.

There is a close relationship between the SARS-CoV-2 virus and lipoproteins, in particular high-density lipo-protein (HDL). The severity of the coronavirus disease 2019 (COVID-19) is inversely correlated with HDL plasma levels. It is known that the SARS-CoV-2 spike (S) protein binds the HDL particle, probably depleting it of lipids and altering HDL function. Based on neutron reflectometry (NR) and the ability of HDL to efflux cholesterol from macrophages, we confirm these observations and further identify the preference of the S protein for specific lipids and the consequent effects on HDL function on lipid exchange ability. Moreover, the effect of the S protein on HDL function differs depending on the individuals lipid serum profile. Contrasting trends were observed for individuals presenting low triglycerides/high cholesterol serum levels (LTHC) compared to high triglycerides/ high cholesterol (HTHC) or low triglycerides/low cholesterol serum levels (LTLC). Collectively, these results suggest that the S protein interacts with the HDL particle and, depending on the lipid profile of the infected individual, it impairs its function during COVID-19 infection, causing an imbalance in lipid metabolism.

The front cover image illustrates the successful production of “heavy” deuterated linoleic acid. Deuterium was installed at the beginning of the synthesis via hydrothermal deuteration of readily available saturated fatty acids. The fatty acids were stitched together to ultimately afford the requisite cis,cis-skipped diene of linoleic acid. Deuterated linoleic acid is required for the production of labelled biologically relevant linoleoyl lipids, whereby deuteration facilitates various experimental techniques. This was demonstrated by the synthesis of tail deuterated 1-palmitoyl-d31-2-linoleoyl-d31-sn-glycero-3-phosphocholine (PLPC-d62). Details can be found in the Research Article by Darwish and co-workers (M. Moir, N. R. Yepuri, D. L. Marshall, S. J. Blanksby, T. A. Darwish, Adv. Synth. Catal. 2022, 364, 3670–3681; DOI: 10.1002/adsc.202200616).

The use of NiO nanoparticles as asphaltene co-precipitant additives is studied to improve the upgraded oil's properties and potentially reduce the solvent-to-oil ratio for the in-situ upgrading of heavy oils via solvent deasphalting. Asphaltene content, solubility profile, and C7-deasphalting laboratory experiments were carried out to evaluate the efficiency of the nanomaterial. Results showed that nickel oxide nanoparticles increased the amount of asphaltenes in the 15-18% range with respect to the case without additive at the same solvent-to crude ratio. In the presence of the NiO nanoparticles, improvements on the upgraded crude oil properties were found with an average 17.1 degrees API gravity (16% increase) and a viscosity of similar to 2370 cSt (similar to 16% reduction) vs. the case without additive. These results demonstrate the usefulness of using nickel oxide nanoparticles to further enhance the upgraded crude oil properties for heavy oil upgrading via solvent deasphalting. Based on elemental analysis and spectroscopic techniques (scanning transmission electron microscopy with high angle annular dark field detection, energy dispersive X-ray analysis, Mid-and Far-FT-IR, and X-ray photoelectron spectroscopy), it was found that NiO nanoparticles acted as nucleation sites (agglomerants). A carbon-containing layer from the asphaltene fraction encapsulates the nickel oxide nanoparticles. A plausible mechanism for the interaction of the nanostructured NiO with the C7-asphaltenes was proposed that involves the formation of nanosized Ni-Ocarboxylate or phenolate species on the surface of the nickel oxide nanoparticles.

The conformation of the polycation in the prototypical polymeric ionic liquid (PIL) poly(3-methyl-1-aminopropylimidazolylacrylamide) bis(trifluoromethylsulfonyl)imide (poly(3MAPIm)TFSI) was probed using small-angle neutron scattering (SANS) and ultra-small-angle neutron scattering (USANS) at 25 °C and 80 °C. Poly(3MAPIm)TFSI contains microvoids which lead to intense low q scattering that can be mitigated using mixtures of hydrogen- and deuterium-rich materials, allowing determination of the polycation conformation and radius of gyration (Rg). In the pure PIL, the polycation adopts a random coil conformation with Rg = 52 ± 0.5 Å. In contrast to conventional polymer melts, the pure PIL is not a theta solvent for the polycation. The TFSI- anions, which comprise 48% v/v of the PIL, are strongly attracted to the polycation and act like small solvent molecules which leads to chain swelling analogous to an entangled, semi-dilute, or concentrated polymer solution in a good solvent.

Herein, we report a gram-scale synthesis of perdeuterated linoleic acid-d(31). The starting materials for the synthesis are two saturated fatty acids, azelaic acid-d(14) and pentanoic acid-d(9), which can be obtained by metal catalysed hydrothermal hydrogen-deuterium exchange. The synthesis utilises the fatty acids directly via decarboxylative coupling. Copper catalysed coupling of a terminal alkyne intermediate with a propargyl bromide derivative affords a skipped diyne, which can be reduced using P-2 nickel to obtain the desired cis,cis-diene geometry. The subsequent synthesis of the tail-deuterated phospholipid, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine-d(62) (PLPC-d(62)) is also described. Optimised reaction conditions were developed to access this phospholipid and its regioisomeric purity was characterised by two complementary mass spectrometry techniques.

Abstract Cytochrome P450 monooxygenase enzymes are versatile catalysts, which have been adapted for multiple applications in chemical synthesis. Mutation of a highly conserved active site threonine to a glutamate can convert these enzymes into peroxygenases that utilise hydrogen peroxide (H2O2). Here, we use the T252E‐CYP199A4 variant to study peroxide‐driven oxidation activity by using H2O2 and urea‐hydrogen peroxide (UHP). We demonstrate that the T252E variant has a higher stability to H2O2 in the presence of substrate that can undergo carbon‐hydrogen abstraction. This peroxygenase variant could efficiently catalyse O‐demethylation and an enantioselective epoxidation reaction (94 % ee). Neither the monooxygenase nor peroxygenase pathways of the P450 demonstrated a significant kinetic isotope effect (KIE) for the oxidation of deuterated substrates. These new peroxygenase variants offer the possibility of simpler cytochrome P450 systems for selective oxidations. To demonstrate this, a light driven H2O2 generating system was used to support efficient product formation with this peroxygenase enzyme.

A new method based on liquid scintillation counting (LSC) was developed to determine the biocarbon content in liquid fuels via radiocarbon analysis. The method has a simple and straightforward procedure that requires no sample preparation, making it well suited for use in a refinery laboratory setting. Using the gasoline, diesel, and jet fuel blends made from renewable naphtha and diesel in petroleum (ranging from 0.5 to 100%), we demonstrate that moderately colored samples and sample luminescence do not influence the accuracy, nor does the method require any additional sample preparation. Statistical analysis of the data shows a very good correlation between the LSC method and accelerator mass spectrometry (AMS), with a sub 1% biocarbon detection limit for the LSC method.

The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50 = 19 nM, CB1R EC50 > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.

Video recording of the manual version of the ASTM D445, Standard Test Method for Kinematic Viscosity of Transparent and Opaque Liquids (and Calculation of Dynamic Viscosity), effectively automated this method, resolved ergonomic concerns, reduced chemical exposure of an operator, drastically reduced probability of errors of the operator, significantly improved productivity, and simplified the analyst training process and work turnover. The accuracy of results is acceptable from the standpoint of the ASTM D445 method.