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Optical control of neuronal activities with photoswitchable nanovesicles

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Abstract

Precise modulation of neuronal activity by neuroactive molecules is essential for understanding brain circuits and behavior. However, tools for highly controllable molecular release are lacking. Here, we developed a photoswitchable nanovesicle with azobenzene-containing phosphatidylcholine (azo-PC), coined ‘azosome’, for neuromodulation. Irradiation with 365 nm light triggers the trans-to-cis isomerization of azo-PC, resulting in a disordered lipid bilayer with decreased thickness and cargo release. Irradiation with 455 nm light induces reverse isomerization and switches the release off. Real-time fluorescence imaging shows controllable and repeatable cargo release within seconds (< 3 s). Importantly, we demonstrate that SKF-81297, a dopamine D1-receptor agonist, can be repeatedly released from the azosome to activate cultures of primary striatal neurons. Azosome shows promise for precise optical control over the molecular release and can be a valuable tool for molecular neuroscience studies.

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References

  1. Dagdeviren, C.; Ramadi, K. B.; Joe, P.; Spencer, K.; Schwerdt, H. N.; Shimazu, H.; Delcasso, S.; Amemori, K. I.; Nunez-Lopez, C.; Graybiel, A. M. et al. Miniaturized neural system for chronic, local intracerebral drug delivery. Sci. Transl. Med. 2018, 10, eaan2742.

    Article  Google Scholar 

  2. Feiner, R.; Dvir, T. Tissue—electronics interfaces: From implantable devices to engineered tissues. Nat. Rev. Mater. 2018, 3, 17076.

    Article  CAS  Google Scholar 

  3. Rao, S. Y.; Chen, R.; LaRocca, A. A.; Christiansen, M. G.; Senko, A. W.; Shi, C. H.; Chiang, P. H.; Varnavides, G.; Xue, J.; Zhou, Y. Remotely controlled chemomagnetic modulation of targeted neural circuits. Nat. Nanotechnol. 2019, 14, 967–973.

    Article  CAS  Google Scholar 

  4. Airan, R. D.; Meyer, R. A.; Ellens, N. P. K.; Rhodes, K. R.; Farahani, K.; Pomper, M. G.; Kadam, S. D.; Green, J. J. Noninvasive targeted transcranial neuromodulation via focused ultrasound gated drug release from nanoemulsions. Nano Lett. 2017, 17, 652–659.

    Article  CAS  Google Scholar 

  5. Wang, J. B.; Aryal, M.; Zhong, Q.; Vyas, D. B.; Airan, R. D. Noninvasive ultrasonic drug uncaging maps whole-brain functional networks. Neuron 2018, 100, 728–738.e7.

    Article  CAS  Google Scholar 

  6. Rapp, T. L.; DeForest, C. A. Targeting drug delivery with light: A highly focused approach. Adv. Drug Deliv. Rev. 2021, 171, 94–107.

    Article  CAS  Google Scholar 

  7. Ellis-Davies, G. C. R. Caged compounds: Photorelease technology for control of cellular chemistry and physiology. Nat. Methods 2007, 4, 619–628.

    Article  CAS  Google Scholar 

  8. Taura, J.; Nolen, E. G.; Cabré, G.; Hernando, J.; Squarcialupi, L.; López-Cano, M.; Jacobson, K. A.; Fernández-Dueñas, V.; Ciruela, F. Remote control of movement disorders using a photoactive adenosine A2A receptor antagonist. J. Control. Release 2018, 283, 135–142.

    Article  CAS  Google Scholar 

  9. Ellis-Davies, G. C. R. Useful caged compounds for cell physiology. Acc. Chem. Res. 2020, 53, 1593–1604.

    Article  CAS  Google Scholar 

  10. Silva, J. M.; Silva, E.; Reis, R. L. Light-triggered release of photocaged therapeutics—Where are we now? J. Control. Release 2019, 298, 154–176.

    Article  CAS  Google Scholar 

  11. Maier, W.; Corrie, J. E. T.; Papageorgiou, G.; Laube, B.; Grewer, C. Comparative analysis of inhibitory effects of caged ligands for the NMDA receptor. J. Neurosci. Methods 2005, 142, 1–9.

    Article  CAS  Google Scholar 

  12. Noguchi, J.; Nagaoka, A.; Watanabe, S.; Ellis-Davies, G. C. R.; Kitamura, K.; Kano, M.; Matsuzaki, M.; Kasai, H. In vivo two-photon uncaging of glutamate revealing the structure-function relationships of dendritic spines in the neocortex of adult mice. J. Physiol. 2011, 589, 2447–2457.

    Article  CAS  Google Scholar 

  13. Li, B. Y.; Wang, Y. Y.; Gao, D.; Ren, S. X.; Li, L.; Li, N.; An, H. L.; Zhu, T. T.; Yang, Y. K.; Zhang, H. L. et al. Photothermal modulation of depression-related ion channel function through conjugated polymer nanoparticles. Adv. Funct. Mater. 2021, 31, 2010757.

    Article  CAS  Google Scholar 

  14. Nakano, T.; Mackay, S. M.; Tan, E. W.; Dani, K. M.; Wickens, J. Interfacing with neural activity via femtosecond laser stimulation of drug-encapsulating liposomal nanostructures. eNeuro 2016, 3, ENEURO.0107–16.2016.

    Article  Google Scholar 

  15. Li, W.; Luo, R. C.; Lin, X. D.; Jadhav, A. D.; Zhang, Z. C.; Yan, L.; Chan, C. Y.; Chen, X. F.; He, J. F.; Chen, C. H. et al. Remote modulation of neural activities via near-infrared triggered release of biomolecules. Biomaterials 2015, 65, 76–85.

    Article  CAS  Google Scholar 

  16. Huu, V. A. N.; Luo, J.; Zhu, J.; Zhu, J.; Patel, S.; Boone, A.; Mahmoud, E.; McFearin, C.; Olejniczak, J.; De Gracia Lux, C. et al. Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye. J. Control. Release 2015, 200, 71–77.

    Article  CAS  Google Scholar 

  17. Kohman, R. E.; Cha, S. S.; Man, H. Y.; Han, X. Light-triggered release of bioactive molecules from DNA nanostructures. Nano Lett. 2016, 16, 2781–2785.

    Article  CAS  Google Scholar 

  18. Veetil, A. T.; Chakraborty, K.; Xiao, K. N.; Minter, M. R.; Sisodia, S. S.; Krishnan, Y. Cell-targetable DNA nanocapsules for spatiotemporal release of caged bioactive small molecules. Nat. Nanotechnol. 2017, 12, 1183–1189.

    Article  CAS  Google Scholar 

  19. Xiong, H. J.; Li, X. Y.; Kang, P. Y.; Perish, J.; Neuhaus, F.; Ploski, J. E.; Kroener, S.; Ogunyankin, M. O.; Shin, J. E.; Zasadzinski, J. A. et al. Near-infrared light triggered-release in deep brain regions using ultra-photosensitive nanovesicles. Angew. Chem. 2020, 132, 8686–8693.

    Article  Google Scholar 

  20. Li, X. Y.; Che, Z. F.; Mazhar, K.; Price, T. J.; Qin, Z. P. Ultrafast near-infrared light-triggered intracellular uncaging to probe cell signaling. Adv. Funct. Mater. 2017, 27, 1605778.

    Article  Google Scholar 

  21. Cabré, G.; Garrido-Charles, A.; Moreno, M.; Bosch, M.; Porta-De-La-Riva, M.; Krieg, M.; Gascón-Moya, M.; Camarero, N.; Gelabert, R.; Lluch, J. M. et al. Rationally designed azobenzene photoswitches for efficient two-photon neuronal excitation. Nat. Commun. 2019, 10, 907.

    Article  Google Scholar 

  22. DiFrancesco, M. L.; Lodola, F.; Colombo, E.; Maragliano, L.; Bramini, M.; Paternò, G. M.; Baldelli, P.; Serra, M. D.; Lunelli, L.; Marchioretto, M. et al. Neuronal firing modulation by a membrane-targeted photoswitch. Nat. Nanotechnol. 2020, 15, 296–306.

    Article  CAS  Google Scholar 

  23. Kellner, S.; Berlin, S. Two-photon excitation of azobenzene photoswitches for synthetic optogenetics. Appl. Sci. 2020, 10, 805.

    Article  CAS  Google Scholar 

  24. Morstein, J.; Dacheux, M. A.; Norman, D. D.; Shemet, A.; Donthamsetti, P. C.; Citir, M.; Frank, J. A.; Schultz, C.; Isacoff, E. Y.; Parrill, A. L. et al. Optical control of lysophosphatidic acid signaling. J. Am. Chem. Soc. 2020, 142, 10612–10616.

    Article  CAS  Google Scholar 

  25. Morstein, J.; Hill, R. Z.; Novak, A. J. E.; Feng, S. H.; Norman, D. D.; Donthamsetti, P. C.; Frank, J. A.; Harayama, T.; Williams, B. M.; Parrill, A. L. et al. Optical control of sphingosine-1-phosphate formation and function. Nat. Chem. Biol. 2019, 15, 623–631.

    Article  CAS  Google Scholar 

  26. Morstein, J.; Romano, G.; Hetzler, B. E.; Plante, A.; Haake, C.; Levitz, J.; Trauner, D. Photoswitchable serotonins for optical control of the 5-HT2A receptor. Angew. Chem., Int. Ed. 2022, 61, e202117094.

    Article  CAS  Google Scholar 

  27. Mukhopadhyay, T. K.; Morstein, J.; Trauner, D. Photopharmacological control of cell signaling with photoswitchable lipids. Curr. Opin. Pharmacol. 2022, 63, 102202.

    Article  CAS  Google Scholar 

  28. Bahamonde, M. I.; Taura, J.; Paoletta, S.; Gakh, A. A.; Chakraborty, S.; Hernando, J.; Fernández-Dueñas, V.; Jacobson, K. A.; Gorostiza, P.; Ciruela, F. Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand. Bioconjug. Chem. 2014, 25, 1847–1854.

    Article  CAS  Google Scholar 

  29. Pernpeintner, C.; Frank, J. A.; Urban, P.; Roeske, C. R.; Pritzl, S. D.; Trauner, D.; Lohmüller, T. Light-controlled membrane mechanics and shape transitions of photoswitchable lipid vesicles. Langmuir 2017, 33, 4083–4089.

    Article  CAS  Google Scholar 

  30. Pritzl, S. D.; Konrad, D. B.; Ober, M. F.; Richter, A. F.; Frank, J. A.; Nickel, B.; Trauner, D.; Lohmüller, T. Optical membrane control with red light enabled by red-shifted photolipids. Langmuir 2022, 38, 385–393.

    Article  CAS  Google Scholar 

  31. Pritzl, S. D.; Urban, P.; Prasselsperger, A.; Konrad, D. B.; Frank, J. A.; Trauner, D.; Lohmüller, T. Photolipid bilayer permeability is controlled by transient pore formation. Langmuir 2020, 36, 13509–13515.

    Article  CAS  Google Scholar 

  32. Urban, P.; Pritzl, S. D.; Konrad, D. B.; Frank, J. A.; Pernpeintner, C.; Roeske, C. R.; Trauner, D.; Lohmüller, T. Light-controlled lipid interaction and membrane organization in photolipid bilayer vesicles. Langmuir 2018, 34, 13368–13374.

    Article  CAS  Google Scholar 

  33. Urban, P.; Pritzl, S. D.; Ober, M. F.; Dirscherl, C. F.; Pernpeintner, C.; Konrad, D. B.; Frank, J. A.; Trauner, D.; Nickel, B.; Lohmueller, T. A lipid photoswitch controls fluidity in supported bilayer membranes. Langmuir 2020, 36, 2629–2634.

    Article  CAS  Google Scholar 

  34. Chander, N.; Morstein, J.; Bolten, J. S.; Shemet, A.; Cullis, P. R.; Trauner, D.; Witzigmann, D. Optimized photoactivatable lipid nanoparticles enable red light triggered drug release. Small 2021, 17, 2008198.

    Article  CAS  Google Scholar 

  35. Ishiba, K.; Morikawa, M. A.; Chikara, C.; Yamada, T.; Iwase, K.; Kawakita, M.; Kimizuka, N. Photoliquefiable ionic crystals: a phase crossover approach for photon energy storage materials with functional multiplicity. Angew. Chem., Int. Ed. 2015, 54, 1532–1536.

    Article  CAS  Google Scholar 

  36. Zhou, H. W.; Xue, C. G.; Weis, P.; Suzuki, Y.; Huang, S. L.; Koynov, K.; Auernhammer, G. K.; Berger, R.; Butt, H. J.; Wu, S. Photoswitching of glass transition temperatures of azobenzene-containing polymers induces reversible solid-to-liquid transitions. Nat. Chem. 2017, 9, 145–151.

    Article  CAS  Google Scholar 

  37. Gagnon, D.; Petryszyn, S.; Sanchez, M.; Bories, C.; Beaulieu, J. M.; De Koninck, Y.; Parent, A.; Parent, M. Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice. Sci. Rep. 2017, 7, 41432.

    Article  CAS  Google Scholar 

  38. Dai, R. J.; Ali, M. K.; Lezcano, N.; Bergson, C. A crucial role for cAMP and protein kinase a in D1 dopamine receptor regulated intracellular calcium transients. Neurosignals 2008, 16, 112–123.

    Article  CAS  Google Scholar 

  39. Jeroen Vermeulen, R.; Drukarch, B.; Rob Sahadat, M. C.; Goosen, C.; Wolters, E. C.; Stoof, J. C. The selective dopamine D1 receptor agonist, SKF 81297, stimulates motor behaviour of MPTP-lesioned monkeys. Eur. J. Pharmacol. 1993, 235, 143–147.

    Article  Google Scholar 

  40. Wu, X.; Jiang, Y. Y.; Rommelfanger, N. J.; Yang, F.; Zhou, Q.; Yin, R. K.; Liu, J. L.; Cai, S.; Ren, W.; Shin, A. et al. Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. Nat. Biomed. Eng. 2022, 6, 754–770.

    Article  CAS  Google Scholar 

  41. Li, J. C.; Duan, H. W.; Pu, K. Y. Nanotransducers for near-infrared photoregulation in biomedicine. Adv. Mater. 2019, 31, 1901607.

    Article  Google Scholar 

  42. Li, X. Y.; Xiong, H. J.; Rommelfanger, N.; Xu, X. Q.; Youn, J.; Slesinger, P. A.; Hong, G. S.; Qin, Z. P. Nanotransducers for wireless neuromodulation. Matter 2021, 4, 1484–1510.

    Article  CAS  Google Scholar 

  43. Lyu, Y.; Xie, C.; Chechetka, S. A.; Miyako, E.; Pu, K. Y. Semiconducting polymer nanobioconjugates for targeted photothermal activation of neurons. J. Am. Chem. Soc. 2016, 138, 9049–9052.

    Article  CAS  Google Scholar 

  44. Yao, C.; Wang, P. Y.; Li, X. M.; Hu, X. Y.; Hou, J. L.; Wang, L. Y.; Zhang, F. Near-infrared-triggered azobenzene-liposome/upconversion nanoparticle hybrid vesicles for remotely controlled drug delivery to overcome cancer multidrug resistance. Adv. Mater. 2016, 28, 9341–9348.

    Article  CAS  Google Scholar 

  45. Zhang, Y.; Zhang, Y.; Song, G. B.; He, Y. L.; Zhang, X. B.; Liu, Y.; Ju, H. X. A DNA-azobenzene nanopump fueled by upconversion luminescence for controllable intracellular drug release. Angew. Chem., Int. Ed. 2019, 58, 18207–18211.

    Article  CAS  Google Scholar 

  46. Klauda, J. B.; Venable, R. M.; Freites, J. A.; O’Connor, J. W.; Tobias, D. J.; Mondragon-Ramirez, C.; Vorobyov, I.; MacKerell, A. D. Jr; Pastor, R. W. Update of the CHARMM all-atom additive force field for lipids:Validation on six lipid types. J. Phys. Chem. B 2010, 114, 7830–7843.

    Article  CAS  Google Scholar 

  47. Phillips, J. C.; Hardy, D. J.; Maia, J. D. C.; Stone, J. E.; Ribeiro, J. V.; Bernardi, R. C.; Buch, R.; Fiorin, G.; Hénin, J.; Jiang, W. et al. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J. Chem. Phys. 2020, 153, 044130.

    Article  CAS  Google Scholar 

  48. Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutchison, G. R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 2012, 4, 17.

    Article  CAS  Google Scholar 

  49. Siriwardane, D. A.; Kulikov, O.; Batchelor, B. L.; Liu, Z. W.; Cue, J. M.; Nielsen, S. O.; Novak, B. M. UV- and thermo-controllable azobenzene-decorated polycarbodiimide molecular springs. Macromolecules 2018, 51, 3722–3730.

    Article  CAS  Google Scholar 

  50. Gutiérrez, I. S.; Lin, F. Y.; Vanommeslaeghe, K.; Lemkul, J. A.; Armacost, K. A.; Brooks III, C. L.; MacKerell, A. D. Jr. Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg. Med. Chem. 2016, 24, 4812–4825.

    Article  Google Scholar 

  51. Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I. et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 2010, 31, 671–690.

    CAS  Google Scholar 

  52. Vanommeslaeghe, K.; MacKerell, A. D. Jr. Automation of the CHARMM General Force Field (CGenFF) I:Bond perception and atom typing. J. Chem. Inf. Model. 2012, 52, 3144–3154.

    Article  CAS  Google Scholar 

  53. Vanommeslaeghe, K.; Raman, E. P.; MacKerell, A. D. Jr. Automation of the CHARMM General Force Field (CGenFF) II: Assignment of bonded parameters and partial atomic charges. J. Chem. Inf. Model. 2012, 52, 3155–3168.

    Article  CAS  Google Scholar 

  54. Yu, W. B.; He, X. B.; Vanommeslaeghe, K.; MacKerell, A. D. Jr. Extension of the CHARMM general force field to sulfonyl-containing compounds and its utility in biomolecular simulations. J. Comput. Chem. 2012, 33, 2451–2468.

    Article  CAS  Google Scholar 

  55. Martínez, L.; Andrade, R.; Birgin, E. G.; Martinez, J. M. PACKMOL: A package for building initial configurations for molecular dynamics simulations. J. Comput. Chem. 2009, 30, 2157–2164.

    Article  Google Scholar 

  56. Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 1996, 14, 33–38.

    Article  CAS  Google Scholar 

  57. Gowers, R. J.; Linke, M.; Barnoud, J.; Reddy, T. J. E.; Melo, M. N.; Seyler, S. L.; Domanski, J.; Dotson, D. L.; Buchoux, S.; Kenney, I. M. MDAnalysis: A Python package for the rapid analysis of molecular dynamics simulations. In Proceedings of the 15th Python in Science Conference, Austin, Texas, USA, 2016.

  58. Michaud-Agrawal, N.; Denning, E. J.; Woolf, T. B.; Beckstein, O. MDAnalysis: A toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 2011, 32, 2319–2327.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially supported by National Science Foundation under award number 2123971 (Z. Q., P. A. S., and S. O. N.), National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number RF1NS110499 (Z. Q., and P. A. S.), and a postdoc research grant from the Phospholipid Research Center (Heidelberg, Germany) to H.X.

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Authors and Affiliations

  1. Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, TX, 75080, USA

    Hejian Xiong, Jonghae Youn, Xiuying Li, Yang Wang & Zhenpeng Qin

  2. Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX, 75080, USA

    Kevin A. Alberto & Steven O. Nielsen

  3. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Jaume Taura & Paul A. Slesinger

  4. Department of Chemistry, New York University, New York, NY, 10012, USA

    Johannes Morstein & Dirk Trauner

  5. Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, 75080, USA

    Zhenpeng Qin

  6. Department of Surgery, The University of Texas at Southwestern Medical Center, Dallas, TX, 75080, USA

    Zhenpeng Qin

  7. Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX, 75080, USA

    Zhenpeng Qin

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  1. Hejian Xiong
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  2. Kevin A. Alberto
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Correspondence to Paul A. Slesinger, Steven O. Nielsen or Zhenpeng Qin.

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Xiong, H., Alberto, K.A., Youn, J. et al. Optical control of neuronal activities with photoswitchable nanovesicles. Nano Res. 16, 1033–1041 (2023). https://doi.org/10.1007/s12274-022-4853-x

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