Nanoparticle biocoating to create ATP-powered swimmers capable of repairing proteins on the fly

In this study, we combine nanotechnology and biotechnology to design a biocompatible propulsion system based on the molecular chaperone Hsp90, a heat-shock protein (Hsp) that, in the presence of adenosine 5'-triphosphate (ATP), undergoes nanoscale conformational changes while trapping and renaturing other proteins. We show how, subjected to ATP availability in the medium, Hsp90-functionalized particles significantly enhance their diffusion motion, being able to achieve ballistic motion, while keeping the ability to restore the activity of surrounding heat-inactivated proteins. This biomechanics-based propulsion mechanism represents a promising strategy for the design of self-propelled nanodevices capable of performing sophisticated tasks in live biological contexts that include sensing the environment, recognizing and capturing, folding, and restoring defective proteins on the fly. In the short term, Hsp90-driven nanodevices could be applied to improve industrial processes that require enzymatic catalysis and high temperatures. But in the medium to long term, this bioactive coating could be used in the design of nanomachines that, like mini-robots, navigate the complex body cavities of biological tissues, deliver therapies and/or remove misfolded proteins in disorders such as Alzheimer's or Parkinson's disease.Acknowledgments: The authors acknowledge the financial support from the Spanish Instituto de Salud Carlos iii, and the European Union FEDER funds under Projects ref. PI22/00030, PI19/00349, from the Spanish Ministerio de Ciencia e Innovacion under project PID2020-119242RB-I00 and the European Union H2020-MSCA-RISE-2019 PEPSA-MATE project. ARR and MARD acknowledge financial support from IDIVAL (PREVAL19/04) and the Xunta de Galicia (2017- ED481A/322) respectively. We also acknowledge IDIVAL projects INNVAL19/12 and INNVAL21/1

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Magnetic micromotors crossing lipid membranes

Nano/micromotors are self-propelled particles that show enhanced motion upon being triggered by a stimulus. Their use in nanomedicine has been widely explored, with special focus on imaging or drug delivery. However, a thorough understanding of the requirements for more efficient locomotion is still lacking. In this paper, we assembled magnetically propelled motors of different sizes (i.e., 0.5, 1 and 4 μm) and surface chemistries (positive charge or PEGylated) and assessed their motion in the presence of giant unilamellar lipid vesicles (GUVs) of varying compositions (zwitterionic, negatively charged and saturated lipids). Unexpectedly, the size does not seem to be the dominating characteristics that governs the ability of the motors to cross lipid membranes. Specifically, the 0.5 μm PEGylated motors have very limited ability to cross the lipid membrane of GUVs due to their non-interacting nature compared to their equally sized positively charged counterparts. Furthermore, membranes made of saturated lipids and, in particular, in combination with a weak magnetic field facilitate motors’ crossing, regardless of their size. The results were validated by in-house data-driven statistical analysis that employs experimental data to allow for the identification of individual motor motion in the ensemble when meeting the lipid membranes. Altogether, we provide insight into motor locomotion when they interact with a biological barrier considering both the entire ensemble and the individual motors, which has the potential to support considerations of future motor designs.</p

Recent advances in nano- and micromotors

Nano- and micromotors are fascinating objects that can navigate in complex fluidic environments. Their active motion can be triggered by external power sources or they can exhibit self-propulsion using fuel extracted from their surroundings. The research field is rapidly evolving and has produced nano/micromotors of different geometrical designs, exploiting a variety of mechanisms of locomotion, being capable of achieving remarkable speeds in diverse environments ranging from simple aqueous solutions to complex media including cell cultures or animal tissue. This review aims to provide an overview of the recent developments with focus on predominantly experimental demonstrations of the various motor designs developed in the past 24 months. First, externally driven motors are discussed followed by considering fuel-driven approaches. Finally, a short future perspective is provided

Microswimmers with heat delivery capacity for 3D Cell spheroid penetration

Micro- and nanoswimmers are a fast emerging concept that changes how colloidal and biological systems interact. They can support drug delivery vehicles, assist in crossing biological barriers, or improve diagnostics. We report microswimmers that employ collagen, a major extracellular matrix (ECM) constituent, as fuel and that have the ability to deliver heat via incorporated magnetic nanoparticles when exposed to an alternating magnetic field (AMF). Their assembly and heating properties are outlined followed by the assessment of their calcium-triggered mobility in aqueous solution and collagen gels. It is illustrated that the swimmers in collagen gel in the presence of a steep calcium gradient exhibit fast and directed mobility. The experimental data are supported with theoretical considerations. Finally, the successful penetration of the swimmers into 3D cell spheroids is shown, and upon exposure to an AMF, the cell viability is impaired due to the locally delivered heat. This report illustrates an opportunity to employ swimmers to enhance tissue penetration for cargo delivery via controlled interaction with the ECM

Double-Fueled Janus Swimmers with Magnetotactic Behavior

Self-propelled particles attract a great deal of attention due to the auspicious range of applications for which nanobots can be used. In a biomedical context, self-propelled swimmers hold promise to autonomously navigate to a desired location in an attempt to counteract cell/tissue defects either by releasing drugs or by performing surgical tasks. The vast majority of prior reports deal with single engine assemblies, often utilizing fuel molecules which are considered to be highly cytotoxic. Herein, we introduce two engines: (1) a motor which couples enzymes (<i>i.e.</i>, glucose oxidase) and inorganic nanoparticles (<i>i.e.</i>, platinum nanoparticles) to gain power and (2) a peptide-fueled trypsin motor. We demonstrate that both engines can induce enhanced diffusion properties of (Janus) particles using bioavailable and completely harmless fuel molecules. By combining both engines on the same carrier, we show self-propelled particles employing two independent engines, using two different fuels. A collaborative enhancement of the swimmer’s diffusion properties upon powering-up both engines simultaneously is observed. Additionally, the incorporation of magnetic nanoparticles allows for the swimmer to move in a magnetic gradient upon applying an external magnetic field, yielding in directional motion of the double-fueled particles. These multiple-fueled biocompatible swimmers are a significant contribution to make them applicable in a biomedical context

Magnetically propelled chained nanocomposites for biologically relevant media exploration

Elongated nanostructures to be remotely and magnetically propelled in biologically relevant media, have gained attention as offering themselves as effective tools or carriers in theragnostics applications. However, the magnetic actuation associated remains challenging due to the lack of mechanical information in the media of interest, taking into account biophysical or biomedical purposes. In this study, we detail the magnetic actuation of magnetically propelled chained nanocomposites considering their dynamics, in which their velocity can be modulated in terms of the viscosity of the medium considered, given a magnetic field gradient. Simpler cases of distilled water, a water/glycerol mixture and a fluid made of cell extracts (imitating the cytosol of cells) of known viscosity are the basis experiments for the study of more complex media inside HeLa cells, murine NIH-3T3 fibroblasts and zebrafish larvae, offering the mechanical information required. The experimental results indicate that the magnetically propelled performance of the chained nanostructures can be precisely controlled in potentially changing scenarios, where drug and heat delivery, magnetic separation, or microfluidic technologies are demanded, using a magnetic field gradient and providing good estimations of the dynamical parameters involved.Acknowledgments: M. A. R.-D. acknowledges financial support from the Xunta de Galicia (Regional Government, Spain) under grant 2017-ED481A/322. P. H. is a recipient of a Predoctoral fellowship (IN606A-2018/019) from Axencia Galega de Innovación (GAIN, Xunta de Galicia). R. P. and A. B. D.-I. are supported by Roche-Chus Joint Unit (IN853B 2018/03) funded by GAIN, Consellería de Economía, Emprego e Industria, Xunta de Galicia. A. B. D.-I. acknowledges financial support from the Ministerio de Economía y Competitividad under Sara Borrell contract. M. L. F. acknowledge the financial support from the Spanish MINECO, Instituto de Salud Carlos III and the European Union FEDER funds under Projects ref. PI16/00496, PI19/00349, DTS19/00033 and the NanoBioApp Network (MINECO-17-MAT2016-81955-REDT). V. S. acknowledges the financial support from the Spanish Ministerio de Ciencia e Innovación under project PID2020-119242-I00 and from the European Union under project H2020-MSCA-RISE-2019 PEPSA-MATE (project number 872233). V. S. acknowledges for funding for open access charge: Universidade de Vigo/CISUG.Magnetic swimmersMagnetophoretic mobilityViscosityZebrafish yolk sa