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DNA nanostructures have evoked great interest as potential therapeutics and diagnostics due to ease and robustness of programming their shapes, site-specific functionalizations and responsive behaviours. However, their utility in biological fluids can be compromised through denaturation induced by physiological salt concentrations and degradation mediated by nucleases. Here we demonstrate that DNA nanostructures coated by oligolysines to 0.5:1 N:P (ratio of nitrogen in lysine to phosphorus in DNA), are stable in low salt and up to tenfold more resistant to DNase I digestion than when uncoated. Higher N:P ratios can lead to aggregation, but this can be circumvented by coating instead with an oligolysine-PEG copolymer, enabling up to a 1,000-fold protection against digestion by serum nucleases. Oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability. Thus, oligolysine-PEG is a one-step, structure-independent approach that provides low-cost and effective protection of DNA nanostructures for in vivo applications. The instability of DNA nanostructures in physiological environments has hampered their use as therapeutics and diagnostic agents in in vivo applications. Here, the authors show that coating DNA origami with oligolysine-PEG moieties improves their pharmacokinetic properties in mouse models.

The cellular machinery performs millions of complex reactions with extreme precision at nanoscale. From studying these reactions, scientists have become inspired to build artificial nanosized molecular devices with programmed functions. One of the fundamental tools in designing and creating these nanodevices is molecular self-assembly. In nature, deoxyribonucleic acid (DNA) is inarguably one of the most remarkable self-assembling molecules. Governed by the Watson-Crick base-pairing rules, DNA assembles with a structural reliability and predictability based on sequence composition unlike any other complex biological polymer. This consistency has enabled rational design of hundreds of two- and three-dimensional shapes with a molecular precision and homogeneity not preceded by any other known technology at the nanometer scale. During the last two decades, DNA nanotechnology has undergone a rapid evolution pioneered by the work of Nadrian Seeman (Kallenbach et al 1983 Nature 205 829-31). Especially the introduction of the versatile DNA Origami technique by Rothemund (2006 Nature 440 297-302) led to an efflorescence of new DNA-based self-assembled nanostructures (Andersen et al 2009 Nature 459 73-6, Douglas et al 2009 Nature 459 414-8, Dietz et al 2009 Science 325 725-30, Han et al 2011 Science 332 342-6, Iinuma et al 2014 Science 344 65-9), and variations of this technique have contributed to an increasing repertoire of DNA nanostructures (Wei et al 2012 Nature 485 623-6, Ke et al 2012 Science 338 1177-83, Benson et al 2015 Nature 523 441-4, Zhang et al 2015 Nat. Nanotechnol. 10 779-84, Scheible et al 2015 Small 11 5200-5). These advances have naturally triggered the question: What can these DNA nanostructures be used for? One of the leading proposals of use for DNA nanotechnology has been in biology and biomedicine acting as a molecular 'nanorobot' or smart drug interacting with the cellular machinery. In this review, we will explore and examine the perspective of DNA nanotechnology for such use. We summarize which requirements DNA nanostructures must fulfil to function in cellular environments and inside living organisms. In addition, we highlight recent advances in interfacing DNA nanostructures with biology.

: Within the field of personalized medicine there is an increasing focus on designing flexible, multifunctional drug delivery systems that combine high efficacy with minimal side effects, by tailoring treatment to the individual. : We synthesized a chemically stabilized ~4 nm nucleic acid nanoscaffold, and characterized its assembly, stability and functional properties and . We tested its flexibility towards multifunctionalization by conjugating various biomolecules to the four modules of the system. The pharmacokinetics, targeting capability and bioimaging properties of the structure were investigated in mice. The role of avidity in targeted liver cell internalization was investigated by flow cytometry, confocal microscopy and by fluorescent scanning of the blood and organs of the animals. : We have developed a nanoscaffold that rapidly and with high efficiency can self-assemble four chemically conjugated functionalities into a stable, -applicable system with complete control of stoichiometry and site specificity. The circulation time of the nanoscaffold could be tuned by functionalization with various numbers of polyethylene glycol polymers or with albumin-binding fatty acids. Highly effective hepatocyte-specific internalization was achieved with increasing valencies of tri-antennary galactosamine (triGalNAc) and . : With its facile functionalization, stoichiometric control, small size and high serum- and thermostability, the nanoscaffold presented here constitutes a novel and flexible platform technology for theranostics.

This paper provides the first chronology for the deep ice core from the East Greenland Ice-core Project (EGRIP) over the Holocene and the late last glacial period. We rely mainly on volcanic events and common peak patterns recorded by dielectric profiling (DEP) and electrical conductivity measurement (ECM) for the synchronization between the EGRIP, North Greenland Eemian Ice Drilling (NEEM) and North Greenland Ice Core Project (NGRIP) ice cores in Greenland. We transfer the annual-layer-counted Greenland Ice Core Chronology 2005 (GICC05) from the NGRIP core to the EGRIP ice core by means of 381 match points, typically spaced less than 50 years apart. The NEEM ice core has previously been dated in a similar way and is only included to support the match-point identification. We name our EGRIP timescale GICC05-EGRIP-1. Over the uppermost 1383.84 m, we establish a depth–age relationship dating back to 14 967 years b2k (years before the year 2000 CE). Tephra horizons provide an independent validation of our match points. In addition, we compare the ratio of the annual layer thickness between ice cores in between the match points to assess our results in view of the different ice-flow patterns and accumulation regimes of the different periods and geographical regions. For the next years, this initial timescale will be the basis for climatic reconstructions from EGRIP high-resolution proxy data sets, e.g. stable water isotopes, chemical impurity or dust records.

An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers in the circulation, and it is stabilized by hexamer formation in the presence of zinc ions during storage in the pancreatic β-cell. Due to the transient nature of insulin dimer, direct investigation of this important form is inherently difficult. To address the relationship between insulin oligomerization and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further oligomerization to form the structural equivalent of the classical hexamer. The covalently linked dimer neither bound to the insulin receptor, nor induced a metabolic response in vitro. However, it was extremely thermodynamically stable and did not form amyloid fibrils when subjected to mechanical stress, underlining the importance of oligomerization for insulin stability.

This paper provides the first chronology for the deep ice core from the East Greenland Ice-core Project (EGRIP) over the Holocene and the late last glacial period. We rely mainly on volcanic events and common peak patterns recorded by dielectric profiling (DEP) and electrical conductivity measurement (ECM) for the synchronization between the EGRIP, North Greenland Eemian Ice Drilling (NEEM) and North Greenland Ice Core Project (NGRIP) ice cores in Greenland. We transfer the annual-layer-counted Greenland Ice Core Chronology 2005 (GICC05) from the NGRIP core to the EGRIP ice core by means of 381 match points, typically spaced less than 50 years apart. The NEEM ice core has previously been dated in a similar way and is only included to support the match-point identification. We name our EGRIP timescale GICC05-EGRIP-1. Over the uppermost 1383.84 m, we establish a depth–age relationship dating back to 14 967 years b2k (years before the year 2000 CE). Tephra horizons provide an independent validation of our match points. In addition, we compare the ratio of the annual layer thickness between ice cores in between the match points to assess our results in view of the different ice-flow patterns and accumulation regimes of the different periods and geographical regions. For the next years, this initial timescale will be the basis for climatic reconstructions from EGRIP high-resolution proxy data sets, e.g. stable water isotopes, chemical impurity or dust records.

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented GHB ligands as the first small molecules selectively targeting the CaMKIIα hub, a domain primarily responsible for holoenzyme oligomerisation, with an emerging functional role. Here, we report that the GHB ligand, HOCPCA, improves sensorimotor function after experimental stroke in mice when administered at clinically relevant time and in combination with alteplase. We observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated the ischemia-specific expression of a constitutively active CaMKII kinase fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. HOCPCA's selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy. Competing Interest Statement The University of Copenhagen and Otago Innovation Ltd. have licensed patent rights (EP 3 746 064) for the use of HOCPCA in acute brain injury to Ceremedy Ltd., of which P.W. is a co-founder.