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

Abstract

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.

Angiopoietin-1 Mimetic Nanoparticles for Restoring the Function of Endothelial Cells as Potential Therapeutic for Glaucoma

“…By decreasing the amount of longer functionalized polymer chains while increasing the amount of shorter polymer chains at the same time, it was possible to prepare NPs of varying surface ligand densities and to modulate NP size. Additionally, this approach allows the ligand to protrude from the particle surface and be more accessible for receptor interaction [32][33][34] because ligands have a higher flexibility when the distance between each ligand increases (Figure 2A) [21]. Ligand flexibility is of utmost importance to allow for binding of one particle to multiple receptors at the same time inducing Tie2 receptor clustering and finally, phosphorylation.…”

“…MeO-PEG 2k -PLA 10k and COOH-PEG 5k -PLA 10k block copolymers were synthesized via a ring-opening polymerization as described previously [33]. The molecular weight of the polymers was determined by NMR spectroscopic analysis in deuterated chloroform at 295 K using a Avance 400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany; Figure S2).…”

Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

“…In the first group, free D WSW peptide (150 μL, 1 mg/mL) was injected 1 h before the experiment, and then 150 μL of DiR- D WSW-CCM-(PTX)NS was injected into the two groups at the same time for in vivo imaging. The blocking of the receptors on the BBB by the D WSW peptide was determined [ [50] , [51] , [52] ].…”

Biomedical nanoparticle design: What we can learn from viruses

“…We therefore introduced a modified recognition concept that was inspired by the cell infiltration strategy of human adenovirus (AdV) [ 177 ]. In order to mimic the stepwise virus-cell interplay of AdV, we implemented a sequential display of two ligands, that was based on the steric shielding of the second, uptake-mediating ligand [ 178 ]. While initial cell attachment of the NP was also mediated via binding of EXP3174 to the AT1R, final NP endocytosis was initiated through a cyclic RGD sequence that activated the integrin receptor α v β 3 .…”

“…However, as the second RGD ligand was attached in closer proximity to the NP core, it could only activate the integrin after a previous binding of the AT1R and a resulting spatial approach of the NP to the cell surface. This two-step ligand display led to a significantly enhanced target cell selectivity of resulting NPs [ 178 ]. Additionally, in vivo accumulation in target mesangial cells was comparable to the influenza A mimetic system, thereby proving the potential of both virus-mimetic concepts.…”