Ferrimagnetic Vortex Nanorings Facilitate Efficient and Safe Deep-Brain Magnetothermal Stimulation in Freely Moving Mice

Abstract

Magnetothermal neuromodulation is a minimally invasive, deep-brain accessible, and tether-free technique. The precisely timed activation of thermosensitive ion channels, such as TRPV1, with local heat generated using magnetic nanoparticles is crucial for efficient neuromodulation. Nevertheless, this technique is greatly hindered by its long stimulus-response time and high safety risks due to the poor heat-generating performance of the nanomediators. Herein, we report the establishment of a ferrimagnetic vortex iron oxide nanoring (FVIO)-mediated magnetothermal neurostimulation technique that is efficient and safe. Compared with widely used superparamagnetic iron oxide nanomediators (SPIOs), the FVIOs triggered Ca²⁺ influx into HEK293T cells and cortical neurons at an Fe concentration of 51 µg mL⁻¹, which is 20.27-fold lower than that needed for SPIOs. In vivo magnetothermal stimulation in the central nucleus of the amygdala of mice further demonstrated that FVIOs with the optimal dose of 0.05 µg evoked fear behaviors with an average latency of 2.51 s, which was 2.3-fold faster than that in the SPIO (0.80 µg)-treated group. More importantly, FVIOs-mediated stimulation not only exhibited negligible histopathological alterations and proinflammatory cytokine expression but also successfully elicited fear behaviors in transgene-free mice. The FVIO-mediated efficient and safe neuromodulation has the potential for future neuroscience exploitation and neurological disease treatment.

Keywords

magnetic nanomaterials / magnetic neural stimulation / magnetogenetics / magnetothermal effect / wireless neuromodulation

References

[1] “Modulating Cell Signalling In Vivo With Magnetic Nanotransducers,” Nature Reviews Methods Primers2 (2022): 93, https://doi.org/10.1038/s43586-022-00185-9.

[2] M. G. Christiansen, A. W. Senko, and P. Anikeeva, “Magnetic Strategies for Nervous System Control,” Annual Review of Neuroscience42 (2019): 271-293, https://doi.org/10.1146/annurev-neuro-070918-050241.

[3] M. Roet, S. A. Hescham, A. Jahanshahi, B. P. F. Rutten, P. O. Anikeeva, and Y. Temel, “Progress in Neuromodulation of the Brain: A Role for Magnetic Nanoparticles?,” Progress in Neurobiology177 (2019): 1-14, https://doi.org/10.1016/j.pneurobio.2019.03.002.

[4] R. Munshi, S. M. Qadri, Q. Zhang, I. C. Rubio, P. del Pino, and A. Pralle, “Magnetothermal Genetic Deep Brain Stimulation of Motor Behaviors in Awake, Freely Moving Mice,” Elife6 (2017): e27069, https://doi.org/10.7554/eLife.27069.

[5] B. Chen, G. Romero, M. G. Christiansen, A. Mohr, and P. Anikeeva, “Wireless Magnetothermal Deep Brain Stimulation,” Science347, no. 6229 (2015): 1477-1480, https://doi.org/10.1126/science.1261821.

[6] S. A. Stanley, J. E. Gagner, S. Damanpour, M. Yoshida, J. S. Dordick, and J. M. Freidman, “Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice,” Science336 (2012): 604-608, https://doi.org/10.1126/science.1216753.

[7] R. Munshi, S. M. Qadri, and A. Pralle, “Transient Magnetothermal Neuronal Silencing Using the Chloride Channel Anoctamin 1 (TMEM16A),” Frontiers in Neuroscience12 (2018): 560.

[8] H. Huang, S. Delikanli, H. Zeng, D. M. Ferkey, and A. Pralle, “Remote Control of Ion Channels and Neurons Through Magnetic-Field Heating of Nanoparticles,” Nature Nanotechnology5 (2010): 602-606, https://doi.org/10.1038/nnano.2010.125.

[9] S. A. Stanley, J. Sauer, R. S. Kane, J. S. Dordick, and J. M. Friedman, “Remote Regulation of Glucose Homeostasis in Mice Using Genetically Encoded Nanoparticles,” Nature Medicine21 (2015): 92-98, https://doi.org/10.1038/nm.3730.

[10] S. A. Stanley, L. Kelly, K. N. Latcha, et al., “Bidirectional Electromagnetic Control of the Hypothalamus Regulates Feeding and Metabolism,” Nature531 (2016): 647-650, https://doi.org/10.1038/nature17183.

[11] D. Rosenfeld, A. W. Senko, J. Moon, et al., “Transgene-free Remote Magnetothermal Regulation of Adrenal Hormones,” Science Advances6 (2020): eaaz3734, https://doi.org/10.1126/sciadv.aaz3734.

[12] X. Long, J. Ye, D. Zhao, and S. J. Zhang, “Magnetogenetics: Remote Non-Invasive Magnetic Activation of Neuronal Activity With a Magnetoreceptor,” Science Bulletin60 (2015): 2107-2119, https://doi.org/10.1007/s11434-015-0902-0.

[13] C. Sebesta, D. T. Hinojosa, B. Wang, et al., “Subsecond Multichannel Magnetic Control of Select Neural Circuits in Freely Moving Flies,” Nature Materials21 (2022): 951-958, https://doi.org/10.1038/s41563-022-01281-7.

[14] B. Torres-Herrero, I. Armenia, M. Alleva, et al., “Remote Activation of Enzyme Nanohybrids for Cancer Prodrug Therapy Controlled by Magnetic Heating,” ACS Nano17 (2023): 12358-12373, https://doi.org/10.1021/acsnano.3c01599.

[15] A. Tay and D. D. Carlo, “Remote Neural Stimulation Using Magnetic Nanoparticles,” Current Medicinal Chemistry24 (2017): 537-548, https://doi.org/10.2174/0929867323666160814000442.

[16] A. M. Zheltikov, “Thermodynamic Limitations on the Temperature Sensitivity of Cell-Membrane Ion Channels: Trouble With Enthalpy Uncertainty,” Journal of Applied Physics123 (2018): 224701, https://doi.org/10.1063/1.5026294.

[17] C. Yang and S. Park, “Nanomaterials-Assisted Thermally Induced Neuromodulation,” Biomedical Engineering Letters11 (2021): 163-170, https://doi.org/10.1007/s13534-021-00193-w.

[18] L. Signorelli, S.-A. Hescham, A. Pralle, and D. Gregurec, “Magnetic Nanomaterials for Wireless Thermal and Mechanical Neuromodulation,” Iscience25 (2022): 105401, https://doi.org/10.1016/j.isci.2022.105401.

[19] J. Grandl, S. E. Kim, V. Uzzell, et al., “Temperature-Induced Opening of TRPV1 Ion Channel is Stabilized by the Pore Domain,” Nature Neuroscience13 (2010): 708-714, https://doi.org/10.1038/nn.2552.

[20] W. Gao, Y. Sun, M. Cai, et al., “Copper Sulfide Nanoparticles as a Photothermal Switch for TRPV1 Signaling to Attenuate Atherosclerosis,” Nature Communications9 (2018): 231, https://doi.org/10.1038/s41467-017-02657-z.

[21] J. Yao, B. Liu, and F. Qin, “Kinetic and Energetic Analysis of Thermally Activated TRPV1 Channels,” Biophysical Journal99 (2010): 1743-1753, https://doi.org/10.1016/j.bpj.2010.07.022.

[22] M. Barbic, “Possible Magneto-Mechanical and Magneto-Thermal Mechanisms of Ion Channel Activation in Magnetogenetics,” Elife8 (2019): e45807, https://doi.org/10.7554/eLife.45807.

[23] M. Meister, “Physical Limits to Magnetogenetics,” Elife5 (2016): e17210, https://doi.org/10.7554/eLife.17210.

[24] X. Yang, E. McGlynn, R. Das, S. P. Paşca, B. Cui, and H. Heidari, “Nanotechnology Enables Novel Modalities for Neuromodulation,” Advanced Materials33 (2021): 2103208, https://doi.org/10.1002/adma.202103208.

[25] G. Romero, M. G. Christiansen, L. S. Barbosa, F. Garcia, and P. Anikeeva, “Localized Excitation of Neural Activity via Rapid Magnetothermal Drug Release,” Advanced Functional Materials26 (2016): 6471-6478, https://doi.org/10.1002/adfm.201602189.

[26] T. A. Le, M. P. Bui, and J. Yoon, “Theoretical Analysis for Wireless Magnetothermal Deep Brain Stimulation Using Commercial Nanoparticles,” International Journal of Molecular Sciences 20, no. 12 (2019): 2873.

[27] P. Keblinski, D. G. Cahill, A. Bodapati, C. R. Sullivan, and T. A. Taton, “Limits of Localized Heating by Electromagnetically Excited Nanoparticles,” Journal of Applied Physics100 (2006): 054305, https://doi.org/10.1063/1.2335783.

[28] S. Del Sol-Fernández, P. Martínez-Vicente, P. Gomollón-Zueco, et al., “Magnetogenetics: Remote Activation of Cellular Functions Triggered by Magnetic Switches,” Nanoscale14 (2022): 2091-2118, https://doi.org/10.1039/D1NR06303K.

[29] L. Liu, B. Huang, Y. Lu, Y. Zhao, X. Tang, and Y. Shi, “Interactions Between Electromagnetic Radiation and Biological Systems,” Iscience27 (2024): 109201, https://doi.org/10.1016/j.isci.2024.109201.

[30] J. Moon, M. G. Christiansen, S. Rao, et al., “Magnetothermal Multiplexing for Selective Remote Control of Cell Signaling,” Advanced Functional Materials30 (2020): 2000577, https://doi.org/10.1002/adfm.202000577.

[31] X. Lu, G. Li, W. Jiao, et al., “Magnetic Nanomaterials-Mediated Neuromodulation,” WIREs Nanomedicine and Nanobiotechnology15 (2023): e1890, https://doi.org/10.1002/wnan.1890.

[32] S. Rao, R. Chen, A. A. LaRocca, et al., “Remotely Controlled Chemomagnetic Modulation of Targeted Neural Circuits,” Nature Nanotechnology14 (2019): 967-973, https://doi.org/10.1038/s41565-019-0521-z.

[33] S. Wang, J. Xu, W. Li, S. Sun, S. Gao, and Y. Hou, “Magnetic Nanostructures: Rational Design and Fabrication Strategies Toward Diverse Applications,” Chemical Reviews122 (2022): 5411-5475, https://doi.org/10.1021/acs.chemrev.1c00370.

[34] C. Liang, X. Zhang, Z. Cheng, M. Yang, W. Huang, and X. Dong, “Magnetic Iron Oxide Nanomaterials: A Key Player in Cancer Nanomedicine,” VIEW1 (2020): 20200046, https://doi.org/10.1002/VIW.20200046.

[35] H. Gavilán, S. K. Avugadda, T. Fernández-Cabada, et al., “Magnetic Nanoparticles and Clusters for Magnetic Hyperthermia: Optimizing Their Heat Performance and Developing Combinatorial Therapies to Tackle Cancer,” Chemical Society Reviews50 (2021): 11614-11667, https://doi.org/10.1039/D1CS00427A.

[36] W. Du, T. Liu, F. Xue, et al., “Fe₃O₄ Mesocrystals With Distinctive Magnetothermal and Nanoenzyme Activity Enabling Self-Reinforcing Synergistic Cancer Therapy,” ACS Applied Material Interfaces12 (2020): 19285-19294, https://doi.org/10.1021/acsami.0c02465.

[37] X. L. Liu, S. Chen, H. Zhang, J. Zhou, H. M. Fan, and X. J. Liang, “Magnetic Nanomaterials for Advanced Regenerative Medicine: The Promise and Challenges,” Advanced Materials31 (2019): e1804922, https://doi.org/10.1002/adma.201804922.

[38] L. Xue, Q. Ye, L. Wu, et al., “Magneto-Mechanical Effect of Magnetic Microhydrogel for Improvement of Magnetic Neuro-Stimulation,” Nano Research16 (2023): 7393-7404, https://doi.org/10.1007/s12274-023-5464-x.

[39] X. Liu, M. Peng, G. Li, et al., “Ultrasonication-Triggered Ubiquitous Assembly of Magnetic Janus Amphiphilic Nanoparticles in Cancer Theranostic Applications,” Nano Letters19 (2019): 4118-4125, https://doi.org/10.1021/acs.nanolett.9b01524.

[40] B. Rezaei, P. Yari, S. M. Sanders, et al., “Magnetic Nanoparticles: A Review on Synthesis, Characterization, Functionalization, and Biomedical Applications,” Small20 (2024): 2304848, https://doi.org/10.1002/smll.202304848.

[41] J. Wu, P. Ning, R. Gao, et al., “Programmable ROS-Mediated Cancer Therapy via Magneto-Inductions,” Advanced Science7 (2020): 1902933, https://doi.org/10.1002/advs.201902933.

[42] X. Liu, Y. Zhang, Y. Wang, et al., “Comprehensive Understanding of Magnetic Hyperthermia for Improving Antitumor Therapeutic Efficacy,” Theranostics10 (2020): 3793-3815, https://doi.org/10.7150/thno.40805.

[43] X. Liu, Y. Zhang, Y. Guo, et al., “Electromagnetic Field-Programmed Magnetic Vortex Nanodelivery System for Efficacious Cancer Therapy,” Advanced Science8 (2021): 2100950, https://doi.org/10.1002/advs.202100950.

[44] X. Li, H. Xiong, N. Rommelfanger, et al., “Nanotransducers for Wireless Neuromodulation,” Matter4 (2021): 1484-1510, https://doi.org/10.1016/j.matt.2021.02.012.

[45] E. Kosari and K. Vafai, “Thermal Tissue Damage Analysis for Magnetothermal Neuromodulation and Lesion Size Minimization,” Brain Multiphysics1 (2020): 100014, https://doi.org/10.1016/j.brain.2020.100014.

[46] H. Liu, R. Sun, L. Wang, et al., “Biocompatible Iron Oxide Nanoring-Labeled Mesenchymal Stem Cells: An Innovative Magnetothermal Approach for Cell Tracking and Targeted Stroke Therapy,” ACS Nano16 (2022): 18806-18821, https://doi.org/10.1021/acsnano.2c07581.

[47] T. Zhang, G. Li, Y. Miao, et al., “Magnetothermal Regulation of in Vivo Protein Corona Formation on Magnetic Nanoparticles for Improved Cancer Nanotherapy,” Biomaterials276 (2021): 121021, https://doi.org/10.1016/j.biomaterials.2021.121021.

[48] X. L. Liu, Y. Yang, C. T. Ng, et al., “Magnetic Vortex Nanorings: A New Class of Hyperthermia Agent for Highly Efficient In Vivo Regression of Tumors,” Advanced Materials27 (2015): 1939-1944, https://doi.org/10.1002/adma.201405036.

[49] J. M. Moscarello and M. A. Penzo, “The Central Nucleus of the Amygdala and the Construction of Defensive Modes Across the Threat-Imminence Continuum,” Nature Neuroscience25 (2022): 999-1008, https://doi.org/10.1038/s41593-022-01130-5.

[50] T. Yang, K. Yu, X. Zhang, et al., “Plastic and Stimulus-specific Coding of Salient Events in the Central Amygdala,” Nature616 (2023): 510-519, https://doi.org/10.1038/s41586-023-05910-2.

[51] H. M. Fahmy, E. M. Aly, F. F. Mohamed, N. A. Noor, and A. A. Elsayed, “Neurotoxicity of Green-Synthesized Magnetic Iron Oxide Nanoparticles in Different Brain Areas of Wistar Rats,” Neurotoxicology77 (2020): 80-93, https://doi.org/10.1016/j.neuro.2019.12.014.

[52] S. Nimpf and D. A. Keays, “Is Magnetogenetics the New Optogenetics?” EMBO Journal36 (2017): 1643-1646, https://doi.org/10.15252/embj.201797177.

[53] J. Lu, X. Gao, S. Wang, et al., “Advanced Strategies to Evade the Mononuclear Phagocyte System Clearance of Nanomaterials,” Exploration3 (2023): 20220045, https://doi.org/10.1002/EXP.20220045.

[54] F. H. Wang, D. K. Kim, T. Yoshitake, et al., “Diffusion and Clearance of Superparamagnetic Iron Oxide Nanoparticles Infused Into the Rat Striatum Studied by MRI and Histochemical Techniques,” Nanotechnology22 (2011): 015103, https://doi.org/10.1088/0957-4484/22/1/015103.

[55] Q. Feng, X. Xu, C. Wei, et al., “The Dynamic Interactions Between Nanoparticles and Macrophages Impact Their Fate in Brain Tumors,” Small17 (2021): e2103600, https://doi.org/10.1002/smll.202103600.

[56] L. Zhang, Z. Liu, Y. Liu, et al., “Ultrathin Surface Coated Water-Soluble Cobalt Ferrite Nanoparticles With High Magnetic Heating Efficiency and Rapid In Vivo Clearance,” Biomaterials230 (2020): 119655, https://doi.org/10.1016/j.biomaterials.2019.119655.

[57] T. Yuan, Y. Yang, W. Zhan, and D. Dini, International Journal of Molecular Sciences24, no. 3 (2023): 2534.

[58] F. Benfenati and G. Lanzani, “Clinical Translation of Nanoparticles for Neural Stimulation,” Nature Reviews Materials6 (2020): 1-4, https://doi.org/10.1038/s41578-020-00267-8.

[59] S. J. McDougall, H. Guo, and M. C. Andresen, “Dedicated C-Fibre Viscerosensory Pathways to Central Nucleus of the Amygdala,” Journal of Physiology595 (2017): 901-917, https://doi.org/10.1113/JP272898.

[60] M. Aurélie and B. Mathieu, “The Expression Pattern of TRPV1 in Brain,” Journal of Neuroscience31 (2011): 13025-13027.

[61] Z. Zhang, Y. You, M. Ge, H. Lin, and J. Shi, “Functional Nanoparticle-enabled Non-genetic Neuromodulation,” Journal of Nanobiotechnology21 (2023): 319, https://doi.org/10.1186/s12951-023-02084-x.

RIGHTS & PERMISSIONS

2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.