Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.

SignificanceSurfaces are gates to control the transport of energy and materials between the gas phase and bulk. For the hydrogen storage, the transport of hydrogen across the surface is recognized as the bottleneck, e.g., 1 H2 in 1,000 impinging a Pd surface penetrates the surface. Here, we demonstrate that alloying the Pd(110) surface with submonolayer amounts of Au dramatically accelerates the hydrogen absorption, by a factor of more than 40. This discovery will lead to enhancement of hydrogen absorption kinetics, thereby improving the performance of hydrogen-purifying membranes and hydrogen-storage materials, which is a key for utilizing hydrogen as a carbon-free energy carrier.

Alloying Pd with Au has remarkable features of enhancement of hydrogen solubility compared to Pd and catalytic activity for reactions such as partial hydrogenation of unsaturated hydrocarbons. A key to understanding these phenomena is clarification of hydrogen behavior in the near-surface region. In the present work, by applying nuclear reaction analysis for high-resolution depth profiling of hydrogen in combination with thermal desorption spectroscopy, we show that hydrogen substantially accumulates in the near-surface region and is absorbed in the bulk of a single-crystal Pd70Au30(110) alloy. We also demonstrate a molecular cap effect of CO, where a small amount of CO adsorption greatly changes the hydrogen absorption and desorption behavior by blocking the entrance/exit channel for hydrogen. These findings lead to understanding and controlling the catalytic activity of the Pd–Au alloy and Pd-related surfaces and also open up a new method to control hydrogen transport across metal surfaces.

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

Rapid and transient expression of in vitro transcribed mRNA (IVT mRNA) in target cells is a current major challenge in genome engineering therapy. To improve mRNA delivery efficiency, a series of amphiphilic polyaspartamide derivatives were synthesized to contain various hydrophobic moieties with cationic diethylenetriamine (DET) moieties in the side chain and systematically compared as mRNA delivery vehicles (or mRNA-loaded polyplexes). The obtained results demonstrated that the side chain structures of polyaspartamide derivatives were critical for the mRNA delivery efficiency of polyplexes. Interestingly, when the mRNA delivery efficiencies (or the luciferase expression levels in cultured cells) were plotted against an octanol–water partition coefficient (log P) as an indicator of hydrophobicity, a log P threshold was clearly observed to obtain high levels of mRNA expression. Indeed, 3.5 orders of magnitude difference in the expression level is observed between −2.45 and −2.31 in log P. This threshold of log P for the mRNA transfection efficiency apparently correlated with those for the polyplex stability and cellular uptake efficiency. Among the polyaspartamide derivatives with log P > −2.31, a polyaspartamide derivative with 11 residues of 2-cyclohexylethyl (CHE) moieties and 15 residues of DET moieties in the side chains elicited the highest mRNA expression in cultured cells. The optimized polyplex further accomplished highly efficient, rapid, and transient IVT mRNA expression in mouse brain after intracerebroventricular and intrathecal injection. Ultimately, the polyplex allowed for the highly efficient target gene deletion via the expression of Streptococcus pyogenes Cas9 nuclease-coding IVT mRNA in the ependymal layer of ventricles in a reporter mouse model. These results demonstrate the utility of log P driven polymer design for in vivo IVT mRNA delivery.

We studied the effect of deposition temperature on the hydrogen distribution and the passivation performance of hydrogenated amorphous silicon (a-Si:H) coated crystalline silicon (c-Si) heterojunctions as a model of high efficiency solar cell structures. Nuclear reaction analysis (NRA) was employed to obtain hydrogen depth profiles of the heterojunctions prepared at temperatures from 80 to 180 °C. The implied open circuit voltage (i-VOC) and carrier lifetime monotonically increased with increasing deposition temperature in the as-deposited samples. NRA clarified that the hydrogen concentration (CH) at the a-Si:H/c-Si interface and in the a-Si:H layer decreased with deposition temperature. The hydrogen concentration around the interface was roughly 3 × 1021 cm-3 for the sample deposited at 180 °C. The NRA results are supplemented by optical constants obtained with spectroscopic ellipsometry (SE). At higher growth temperature, larger refractive indices and extinction coefficients were confirmed by SE analysis, suggesting that fewer hydrogen atoms are incorporated into the a-Si:H layers prepared at higher growth temperature. Furthermore, the passivation performance was enhanced by post deposition annealing (PDA) at 200 °C for 30 min. No significant change of the hydrogen distribution and optical constants was observed after PDA, suggesting that improved passivation is due to a local rearrangement of hydrogen at the molecular level that results in enhanced hydrogenation of dangling bonds.

Nuclear reaction analysis (NRA) via the resonant (1)H((15)N,αγ)(12)C reaction is a highly effective method of depth profiling that quantitatively and non-destructively reveals the hydrogen density distribution at surfaces, at interfaces, and in the volume of solid materials with high depth resolution. The technique applies a (15)N ion beam of 6.385 MeV provided by an electrostatic accelerator and specifically detects the (1)H isotope in depths up to about 2 μm from the target surface. Surface H coverages are measured with a sensitivity in the order of ~10(13) cm(-2) (~1% of a typical atomic monolayer density) and H volume concentrations with a detection limit of ~10(18) cm(-3) (~100 at. ppm). The near-surface depth resolution is 2-5 nm for surface-normal (15)N ion incidence onto the target and can be enhanced to values below 1 nm for very flat targets by adopting a surface-grazing incidence geometry. The method is versatile and readily applied to any high vacuum compatible homogeneous material with a smooth surface (no pores). Electrically conductive targets usually tolerate the ion beam irradiation with negligible degradation. Hydrogen quantitation and correct depth analysis require knowledge of the elementary composition (besides hydrogen) and mass density of the target material. Especially in combination with ultra-high vacuum methods for in-situ target preparation and characterization, (1)H((15)N,αγ)(12)C NRA is ideally suited for hydrogen analysis at atomically controlled surfaces and nanostructured interfaces. We exemplarily demonstrate here the application of (15)N NRA at the MALT Tandem accelerator facility of the University of Tokyo to (1) quantitatively measure the surface coverage and the bulk concentration of hydrogen in the near-surface region of a H2 exposed Pd(110) single crystal, and (2) to determine the depth location and layer density of hydrogen near the interfaces of thin SiO2 films on Si(100).

The adsorption of atomic hydrogen on a rutile TiO 2 (110) surface was investigated by nuclear reaction analysis (NRA), ultraviolet photoelectron spectroscopy (UPS), and conductivity measurements. The TiO 2 (110) surface was annealed in O 2 of 1 × 10 −4 Pa, which is regarded as a quasi-stoichiometric surface. After exposure to atomic hydrogen, UPS showed a localized in-gap state (IGS) at about 0.8 eV below the Fermi level and downward band bending with a decrease in the work function. Along with these changes, the conductivity was increased by 2.9 µS=□. Our results indicate that hydrogen donates electrons to the substrate. The amount of charge transfer and electric conductivity are discussed on the basis of the experimental data.