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Adenovirus-Mimetic Nanoparticles: Sequential Ligand–Receptor Interplay as a Universal Tool for Enhanced In Vitro/In Vivo Cell Identification

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journal contribution
posted on 22.07.2020, 17:04 by Daniel Fleischmann, Sara Maslanka Figueroa, Sebastian Beck, Kathrin Abstiens, Ralph Witzgall, Frank Schweda, Philipp Tauber, Achim Goepferich
Viral infection patterns often rely on precisely coordinated sequences of distinct ligand–receptor interactions, leading in many cases to an outstanding target cell specificity. A successful mimicry of viral targeting strategies to create more site-specific nanoparticles (NPs) would therefore require particle–cell interactions to also be adequately controllable. In the present study, hetero-multivalent block-copolymer NPs present their attached ligands in a sterically controlled manner to create a sequential NP–cell interaction similar to the cell infiltration strategy of human adenovirus type 2. Targeting renal mesangial cells, particles therefore initially bind angiotensin II receptor type 1 (AT1r) on the cell surface via a structurally flexible AT1r antagonist. After a mandatory spatial approach, particle endocytosis is realized via binding of immobile αVβ3 integrins with a previously concealed secondary ligand, thereby creating a stepwise particle–cell interplay of primary NP attachment and subsequent uptake. Manufactured adenovirus-mimetic NPs show great avidity for both target motifs in vitro, leading to a substantial binding as well as subsequent cell uptake into target mesangial cells. Additionally, steric shielding of secondary ligand visibility leads to a highly controllable, sequential ligand–receptor interaction, whereby hetero-functional NPs activate mesangial cell surface integrins only after a successful prior binding to the AT1r. This stepwise cell identification significantly enhances mesangial cell specificity in co-culture assays with different off-target cells. Additionally, described NPs display excellent in vivo robustness by efficiently accumulating in the mesangium upon injection, thereby opening new paths for possible drug delivery applications.