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Christopher P Haycook,1 Joseph A Balsamo,2,3 Evan B Glass,1 Charles H Williams,4 Charles C Hong,5 Amy S Major,3,6 Todd D Giorgio1 1Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; 2Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; 3Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt Medical Center, Nashville, TN 37232, USA; 4Department of Medicine, Division of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; 5Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; 6U.S., Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USACorrespondence: Todd D GiorgioDepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USAEmail todd.d.giorgio@vanderbilt.eduBackground: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab’) antibody fragments to enable targeted delivery of Egm.Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm.Conclusion: This work is the first characterization of Egm’s immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.Keywords: advanced delivery systems, eggmanone, autoimmunity, controlled release |
