title: Interferon alpha-armed nanoparticles trigger rapid and sustained STAT1-dependent anti-viral cellular responses.
abstract: Interferon-α (IFNα) has enormous potential for anti-proliferative and anti-viral treatments. However, clinical success is still hampered due to its limited bioavailability and thus, lack of sustained modulation of disease-relevant protective programs. Consequently, we here examined whether IFNα immobilized on nanoscale ferromagnetic R-Chitosan carriers is capable of inducing rapid and sustained activation of STAT1 signaling. We report the spontaneous formation of a stable nanoparticle-IFNα protein corona, which was exploited to generate IFNα-loaded spheres, obviating the need to specifically couple the cytokine to the nanoparticles (NPs). Notably, comprehensive experimental approaches ensure that formation of the IFNα NP-corona does not affect the biological activity of the cytokine, as STAT1 signaling was efficiently activated. Employing human prostate cancer and melanoma cell models, we found that the intensity and duration of STAT1 phosphorylation as well as the downstream activation of pathobiologically relevant genes were dose and particle dependent. In comparison with free IFNα, IFNα-loaded spheres resulted in a more sustained biologically relevant STAT1 activation, demonstrated also by conferring innate cellular immunity against vesicular stomatitis virus (VSV) infection. For one, our study demonstrates the advantages of biodegradable IFNα-coated R-Chitosan NPs for controlled cytokine release, and thereby improved therapy. Second, we reveal that the permanent presence of IFNα and not just the initial STAT1 phosphorylation ensures sustained IFNα-dependent signaling.
authors: University of Applied Sciences Jena, Department of Medical Engineering and Biotechnology, 07745 Jena, Germany.
authors: Sibyll
authors: S
authors: Pollok
authors: Torsten
authors: T
authors: Ginter
authors: Katharina
authors: K
authors: Günzel
authors: Jana
authors: J
authors: Pieper
authors: Andreas
authors: A
authors: Henke
authors: Roland H
authors: RH
authors: Stauber
authors: Werner
authors: W
authors: Reichardt
authors: Oliver H
authors: OH
authors: Krämer
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate / Q000187:drug effects; D016898:Interferon-alpha / Q000737:chemistry / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D054243:Vesicular Stomatitis / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D016898:Interferon-alpha; D058185:Magnetite Nanoparticles; D050794:STAT1 Transcription Factor; D048271:Chitosan; D053612:Janus Kinases