Impact of interferon-γ on the target cell tropism of nanoparticles

Oliver Zimmer; Melanie Walter; Marius Remmert; Olga Maier; Ralph Witzgall; Achim Goepferich

doi:10.1016/j.jconrel.2023.08.034

Impact of interferon-γ on the target cell tropism of nanoparticles

J Control Release. 2023 Oct:362:325-341. doi: 10.1016/j.jconrel.2023.08.034. Epub 2023 Sep 2.

Authors

Oliver Zimmer¹, Melanie Walter¹, Marius Remmert¹, Olga Maier², Ralph Witzgall², Achim Goepferich³

Affiliations

¹ Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Bavaria 93053, Germany.
² Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Bavaria 93053, Germany.
³ Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Bavaria 93053, Germany. Electronic address: achim.goepferich@ur.de.

PMID: 37598888
DOI: 10.1016/j.jconrel.2023.08.034

Abstract

Interferon-γ (IFN-γ) is well known to reduce the infectivity of viral pathogens by altering their tissue tropism. This effect is induced by upregulation of cholesterol 25-hydroxylase (CH25H). Given the similarity of viral pathogens and ligand-functionalized nanoparticles in the underlying strategy of receptor-mediated cell recognition, it appears conceivable that IFN-γ exceeds similar effects on nanoparticles. Concretely, IFN-γ-induced activation of CH25H could decrease nanoparticle avidity for target cells via depletion of clathrin-coated pits. We hypothesized that this effect would cause deterioration of target-cell specific accumulation of nanoparticles. To prove our hypothesis, we investigated the cell tropism of angiotensin II functionalized nanoparticles (NP_{Lys-Ang II}) in a co-culture system of angiotensin II subtype 1 receptor (AT₁R) positive rat mesangial target cells (rMCs) and AT₁R-negative HeLa off-target cells. In the presence of IFN-γ we observed an up to 5-fold loss of target cell preference for NP_{Lys-Ang II}. Thus, our in vitro results suggest a strong influence of IFN-γ on nanoparticle distribution, which is relevant in the context of nanotherapeutic approaches to cancer treatment, as IFN-γ is strongly expressed in tumors. For the target cell tropism of viruses, our results provide a conclusive hypothesis for the underlying mechanism behind non-directed viral distribution in the presence of IFN-γ.

Keywords: Biodistribution; Cholesterol-25-hydroxylase (CH25H); Interferon-γ; Nano-bio interactions; Preferential uptake; Targeted nanoparticles; Targeting efficiency.