Maartje Bastings1 Hale Bila1

1, EPFL, Lausanne, , Switzerland

Multivalency is a ubiquitous phenomenon in nature. Over the past decades, the fields of nanoparticle and nano-engineering have utilised this concept to achieve targeted delivery, increased specificity and selectivity of therapeutic and diagnostic ligand-functionalized nanoparticles. Numerous systems have been developed yet the translation to clinical success is rare. It has been recognised that a certain threshold concentration / density of ligands on a nanoparticle surface is required to activate or engage biologically relevant signalling; however, detailed quantitative assays on enhanced binding affinities through multivalent ligand presentation are rare.

With a system that is so abundant in nature, and functions flawlessly in amongst others cell signalling and immune protection, it is clear that fundamental design principles for the mechanistic translation of (heterogeneous) multivalency into targeted therapeutic nanoparticles are missing. To understand how to improve these design parameters, we need new analysis methods, better control in nanoparticle ligand presentation and advances in or theoretical models and simulations.

In this study, we started with a proof of concept where fully programmable dendritic nanoparticles interact with well-defined multivalent targets. We choose DNA as material backbone of our particles to ensure perfect programmable control over size, shape and ligand functionality. By spatially matching ligand presentation versus surface receptor density, we demonstrate that control in design outperforms random ligand presentation. In a second next step, we present heterogeneous ligands to target complex multivalency, defined by us as the multivalent interaction between heterogeneous ligand/receptor molecules. We compare these systems with bispecific antibodies and our models will be used to mechanistically and quantitatively study the potential synergy in thier heterogeneous multivalent binding. The system will then be gradually expanded to program more ligands and understand the role of spatial control in cell-matrix binding and cell signalling using integrin targeting ligands. Our novel insights in multivalent binding has the potential to be translated toward improved design of biomaterials and superior diagnostic / therapeutic nanoparticles.