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    Exploiting Rational Assembly to Map Distinct Roles of Regulatory Cues during Autoimmune Therapy
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    • Robert S. Oakes
      Robert S. Oakes
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      United States Department of Veterans Affairs, VA Maryland Health Care System, 10 N. Greene Street, Baltimore, Maryland 21201, United States
      More by Robert S. Oakes
      Orcidhttp://orcid.org/0000-0003-3783-6488
    • Lisa H. Tostanoski
      Lisa H. Tostanoski
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      More by Lisa H. Tostanoski
    • Senta M. Kapnick
      Senta M. Kapnick
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      More by Senta M. Kapnick
    • Eugene Froimchuk
      Eugene Froimchuk
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      More by Eugene Froimchuk
    • Sheneil K. Black
      Sheneil K. Black
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      More by Sheneil K. Black
    • Xiangbin Zeng
      Xiangbin Zeng
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      More by Xiangbin Zeng
    • Christopher M. Jewell*
      Christopher M. Jewell
      Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      United States Department of Veterans Affairs, VA Maryland Health Care System, 10 N. Greene Street, Baltimore, Maryland 21201, United States
      Robert E. Fischell Institute for Biomedical Devices, 5102 A. James Clark Hall, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
      Department of Microbiology and Immunology, University of Maryland Medical School, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, Maryland 21201, United States
      Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene Street, Baltimore, Maryland 21201, United States
      *Email: [email protected], [email protected]
      More by Christopher M. Jewell
      Orcidhttp://orcid.org/0000-0002-6668-6928
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    ACS Nano

    Cite this: ACS Nano 2021, 15, 3, 4305–4320
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    https://doi.org/10.1021/acsnano.0c07440
    Published March 1, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c07440.

    • Figure S1: Dose-dependent control of inflammatory pathways. Figure S2: Dose-dependent suppression of paralysis in EAE model of MS. Figure S3: Charge approximations for components and surface charge and size of immune complexes. Figure S4: GpG in complexes suppresses inflammatory gene expression. Figure S5: GpG in complexes inhibits upstream Myd88 gene expression. Figure S6: GpG in complexes did not impact Ccl22 and Il4 gene expression. Figure S7: Dose matching to isolate the role of each component. Figure S8: Treatments require myelin self-antigen to suppress autoimmune driven paralysis. Figure S9: GpG restrains CpG agonist function in IFN regulatory genes in vitro (PDF)

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    This article is cited by 15 publications.

    1. Rebeca T. Stiepel, Sean R. Simpson, Nicole Rose Lukesh, Denzel D. Middleton, Dylan A. Hendy, Luis Ontiveros-Padilla, Stephen A. Ehrenzeller, Md Jahirul Islam, Erik S. Pena, Michael A. Carlock, Ted M. Ross, Eric M. Bachelder, Kristy M. Ainslie. Induction of Antigen-Specific Tolerance in a Multiple Sclerosis Model without Broad Immunosuppression. ACS Nano 2025, 19 (3) , 3764-3780. https://doi.org/10.1021/acsnano.4c14698
    2. Marian A. Ackun-Farmmer, Marina Willson Shirkey, Robert S. Oakes, Shrey Alpeshkumar Shah, Camilla Edwards, Senta Kapnick, Sean T. Carey, Alexis Yanes, Jonathan Bromberg, Christopher M. Jewell. Engineered Immune Constructs Alter Antigen-Specific Immune Tolerance and Confer Durable Protection in Myelin-Driven Autoimmunity. ACS Nano 2024, 18 (46) , 31780-31793. https://doi.org/10.1021/acsnano.4c06667
    3. Camilla Edwards, Sean T. Carey, Christopher M. Jewell. Harnessing Biomaterials to Study and Direct Antigen-Specific Immunotherapy. ACS Applied Bio Materials 2023, 6 (6) , 2017-2028. https://doi.org/10.1021/acsabm.3c00136
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    5. Joshua M. Gammon, Sean T. Carey, Vikas Saxena, Haleigh B. Eppler, Shannon J. Tsai, Christina Paluskievicz, Yanbao Xiong, Lushen Li, Marian Ackun-Farmmer, Lisa H. Tostanoski, Emily A. Gosselin, Alexis A. Yanes, Xiangbin Zeng, Robert S. Oakes, Jonathan S. Bromberg, Christopher M. Jewell. Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-36225-5
    6. Weifan Ye, Yiwen Jia, Hongze Ren, Yujie Xie, Meihua Yu, Yu Chen. Regulation of Antigen‐Specific Immunotherapy with Nanomaterials. Advanced NanoBiomed Research 2023, 3 (12) https://doi.org/10.1002/anbr.202300068
    7. Camilla Edwards, Shrey. A. Shah, Thomas Gebhardt, Christopher M. Jewell. Exploiting Unique Features of Microneedles to Modulate Immunity. Advanced Materials 2023, 35 (52) https://doi.org/10.1002/adma.202302410
    8. Brooke A. Jackson Hoffman, Elizabeth A. Pumford, Amaka I. Enueme, Kirsten L. Fetah, Olivia M. Friedl, Andrea M. Kasko. Engineered macromolecular Toll-like receptor agents and assemblies. Trends in Biotechnology 2023, 41 (9) , 1139-1154. https://doi.org/10.1016/j.tibtech.2023.03.008
    9. Camilla Edwards, Robert S. Oakes, Christopher M. Jewell. Tuning innate immune function using microneedles containing multiple classes of toll-like receptor agonists. Nanoscale 2023, 15 (19) , 8662-8674. https://doi.org/10.1039/D3NR00333G
    10. Sean T. Carey, Christopher Bridgeman, Christopher M. Jewell. Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps. Advanced Science 2023, 10 (8) https://doi.org/10.1002/advs.202205105
    11. Marian A. Ackun-Farmmer, Christopher M. Jewell. Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity. Advanced NanoBiomed Research 2023, 3 (3) https://doi.org/10.1002/anbr.202200135
    12. Marian Ackun-Farmmer, Christopher M. Jewell. Enhancing the functionality of self-assembled immune signals using chemical crosslinks. Frontiers in Immunology 2023, 14 https://doi.org/10.3389/fimmu.2023.1079910
    13. Michelle L. Bookstaver, Qin Zeng, Robert S. Oakes, Senta M. Kapnick, Vikas Saxena, Camilla Edwards, Nishedhya Venkataraman, Sheneil K. Black, Xiangbin Zeng, Eugene Froimchuk, Thomas Gebhardt, Jonathan S. Bromberg, Christopher M. Jewell. Self‐Assembly of Immune Signals to Program Innate Immunity through Rational Adjuvant Design. Advanced Science 2023, 10 (1) https://doi.org/10.1002/advs.202202393
    14. Shrey A. Shah, Robert S. Oakes, Senta M. Kapnick, Christopher M. Jewell. Mapping the Mechanical and Immunological Profiles of Polymeric Microneedles to Enable Vaccine and Immunotherapy Applications. Frontiers in Immunology 2022, 13 https://doi.org/10.3389/fimmu.2022.843355
    15. Sean T. Carey, Joshua M. Gammon, Christopher M. Jewell. Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways. Drug Delivery and Translational Research 2021, 11 (6) , 2468-2481. https://doi.org/10.1007/s13346-021-01075-5
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    ACS Nano

    Cite this: ACS Nano 2021, 15, 3, 4305–4320
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.0c07440
    Published March 1, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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