Selective multivalent targeting and cell-adhesion

Selective multivalent targeting and cell-adhesion

Multivalency is a unique concept found in nature, where multiple interactions between ligands and receptors are combined to increase overall binding strength and kinetic stability. The multivalent combination of weak ligand-receptor interactions allows to tune the performance of the resulting interaction network. This strength in numbers principle is fundamental to the spatio-temporal control over biological activity in living systems. We explore how we can benefit from the structural precision provided by DNA to design materials that show unique binding profiles toward their cell-surface targets. We correlate our experimental data to new binding models to further analyze and understand how control in nanoparticle design parameters can be used to program binding affinity for the next generation targeting nanoparticles and biomaterials.

Integrins are transmembrane receptors that mediate cell adhesion and are vital in tissue engineering. To date 24 different integrin heterodimers have been identified to respectively distinguish extracellular matrix (ECM) recognition epitopes via multivalent and dynamic receptor clustering. Material interfaces have been made bioadhesive through display of the RGD peptide sequence found on fibronectin (FN), a polymer of the ECM. A minimum spacing of 58 nm has been found critical to ensure a functional cell-material interaction. Integrins are upregulated in diseased cells including many cancers, thus insights in their dynamic spatial organization is crucial in developing targeted therapeutic materials.

Current material interfaces fail to perform a quantitative biospecific in vitro analysis of the spatial parameters in material-integrin signalling. This is caused by inherent polydispersity that arises from lack of control in synthesis at the nanoscale, resulting in a distribution in the presentation of ligands. Therefore, a programmable, modular system with nanometer precision is vital. DNA based nanotechnology afford the nanoscale control paramount in elucidating the role of spatially controlled ligand presentation in integrin signalling. Capitalizing on the nanoscale control of ligand presentation afforded by the DNA nanotechnology platform, we develop material interfaces with functionality that are indistinguishable from nature. When our ECM-mimicking nanostructures are integrated in hydrogels, we anticipate control over the self-assembly of dynamic materials that display unique super-selectivity toward cell adhesion.