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WIREs Nanomed Nanobiotechnol
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Remote control of signaling pathways using magnetic nanoparticles

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Our ability to quantitatively control the spatiotemporal properties of cellular information processing is key for understanding biological systems at both mechanistic and systemic level. In this context, magnetic field offers a relevant strategy of control over cellular processes that broaden the toolbox currently available in cell biology. Among the increasing number of methods, we will focus on recent advances based on magnetic nanoparticles conjugated to proteins to trigger specific signaling pathways and cellular processes. Extracellular or intracellular manipulations of nanoparticles permit magnetic control of ion channels and membrane receptor activation, protein positioning within cells and cytoskeleton spatial engineering. These approaches provide powerful strategies to examine the organization principles of living cells. WIREs Nanomed Nanobiotechnol 2015, 7:342–354. doi: 10.1002/wnan.1313 This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Perturbing protein activity with chemicals, light, or magnetic field. Schematic of current methods used to examine cell functions upon perturbations. (a) The use of small molecules is relatively simple and allows the application of very fast perturbations (second to minute) to examine molecular processes. Perturbations mediated by light offers a control over protein function based on genetically encoded methods, and should improved the spatial resolution at the cell level. (b) Remote control of cellular processes mediated by magnetic nanoparticles. Magnetic nanoparticles targeting specific biomolecules can be used to trigger signaling activities either by activating ion channels or receptors at the cell membrane, or by modifying the spatiotemporal intracellular distribution of signaling proteins.
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Engineering spatiotemporal gradient of signaling proteins involved in microtubule regulation. (a) Principle of the experiment. Magnetic force is used to generate a gradient of bioconjugated nanoparticles. (b) Top: Observation of fluorescent magnetic nanoparticles within Xenopus egg extracts encapsulated inside a droplet in the absence (left) or upon application of a magnetic field (right). Bottom: Corresponding fluorescent intensity and nanoparticle concentration. (c) Left: Observation of an aster in an homogeneous Ran environment. Right: Observation of an aster (grey) in a Ran‐mNP gradient (green). (d) Models of aster off‐centering. First mechanism: Ran‐mNP gradient enhances microtubule polymerization resulting in the generation of pushing forces (top). Second mechanism: Ran‐mNP gradient asymmetries dyneins activity resulting in the generation of pulling forces (bottom).
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Magnetic control of actin filament nucleation. Magnetic nanoparticles were functionalized in situ using HaloTag technology with TIAM1, the guanine exchange factor activating Rac1 in NIH3T3 cells and involved in actin meshwork formation. Micromanipulations of TIAM‐mNPs showed that whereas Rac1 was activated at the membrane everywhere in the cells, F‐actin meshwork formation was only detected when the mNPs was brought in protrusive areas characterizing the lamellipodium of cells.
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Magnetic control of microtubule nucleation and assembly. (a) Simplified schematic of the RCC1/Ran signaling network involved in microtubule nucleation and regulation during mitosis. RCC1 promotes conversion from the GDP (inactive) to GTP (active) conformations of Ran. Interactions between RanGTP and importin‐β induce the release of MAPs such as TPX2, which consequently trigger microtubule nucleation and regulation. (b) Microtubule nucleation and aster assembly are ultrasensitive to the concentration of RanGTP and Ran bound to nanoparticles. (c) Principle of the spatial biochemical switch triggering microtubule nucleation. A gradient of magnetic field is used to direct and concentrate the nanoparticles to a restricted location, and on surpassing the RanGTP concentration threshold will trigger the signaling cascade leading to microtubule assembly. (d) Microtubule nucleation induced by accumulation of Ran‐mNPs under a magnetic field: visualization of Ran–mNP accumulation under bright‐field illumination (left) and microtubule observation using fluorescence microscopy (right) (droplet size, 50 µm). (e) Example of microtubule organization that does not co‐localize with RCC1–mNP accumulation. Visualization of RCC1‐mNP accumulation under bright‐field illumination (left) and microtubule observation using fluorescence microscopy (right) Scale bar, 10 µm. (f) Schematic representation of microtubule nucleation localization induced by Ran‐mNPs or RCC1‐mNPs.
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Magnetic actuation of ion channels and receptors. (a) Magnetic nanoparticles were used to target mechanosensitive ion channels. Upon the application of a gradient of magnetic field, magnetic forces are applied to the loop region of the channel inducing its opening and triggering ion influx. (b) Nanoparticles bound to a single ligand were used to target cell receptors. Upon magnetic actuation, the nanoparticles aggregates through dipolar interactions, which eventually promotes intracellular signaling. (c) The application of radiofrequency magnetic field promotes the local increase of temperature at the nanoparticle surface, resulting in the opening of a temperature‐sensitive ion channel and triggering ionic influx controlling downstream intracellular signaling.
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Magnetic control of neuron motility. (a) Magnetic nanoparticles were conjugated to anti‐TrkB antibody, that allows TrkB activation and specific loading of magnetic nanoparticles into signaling endosomes. After endocytosis, magnetic endosomes were transported through active process to the neurites and the growth cone. (b) Magnetic field was used to control spatial localization of TrkB endosomes. Without magnetic field, TrkB endosomes induced normal growth cone motility and neurite growth (left). Using highly localized gradient of magnetic field, the trafficking of signaling endosomes containing mNPs was perturbed inducing the arrest of the growth cone motility.
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Nanotechnology Approaches to Biology > Cells at the Nanoscale
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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