Selective integrin targeting with DNA-based nanomaterials

Targeting cells specific to type and state remains a challenge in developing effective therapies, sensitive diagnostics, also robust and versatile tissue engineering. A promising strategy is to focuses on improving the inherent selectivity of the targeting system through precise orchestration of ligand-receptor interactions. Integrin receptors present themselves as a strategic target as their expression has been reported to be regulated across cell types and states. The principle of super-selectivity permits the selective targeting of integrin receptors above a threshold concentration in high valency and relative low affinity systems, leaving sparser counterparts unaffected. Here, we demonstrate that DNA based scaffolds with rigid ligand nanoscale spatial presentation can be designed to discriminate between adhesions by varying RGD ligand spacing targeting integrin ⍺5β1 receptors. We begin by modelling integrin ⍺5β1 receptors nearest neighbour distributions across HUVEC, CHO and HeLa cells. Targeting spacings in the sub-60nm reveal trends in binding efficacies based on cell type and activation state. An ensuing study of HUVEC response to local ligand geometries of varying global inter-geometry spacings presented on higher valency DNA scaffolds randomly immobilised result in two distinct adhesion cluster formations. Our findings open avenues in the design of super-selective targeting elements, besides providing insight on the regulation of integrin receptors on the cell surface across different cell types. Parameters for ligand presentation at the sub-adhesion scale affords selective cell engagement in biomaterial presentation.