Directing nanoscale particles to strongly adhere to cancer cells and tissues under hydrodynamic flow in vivo is a challenging biophysical problem with important clinical implications. A common approach uses antibodies conjugated to nanoparticles to impart binding specificity, however, when exposed to mechanical shear stress antibodies are known to unbind at extremely low forces (<150 pN)1-3. This problem can occur even when antibodies are selected for high-affinity (e.g., KD < 1 nM) interactions at equilibrium. The goal of this research is therefore to engineer artificial binding proteins that form mechanically stable complexes with their target ligands for applications in nanoparticle-based drug delivery and bioimaging. I will focus on non-antibody (nAb) binding scaffolds (e.g., anticalin, affibody and DARPin) that will be optimized through two disparate yet complementary approaches: (1) geometrics and (2) genetics. By mechanically enhancing binding interactions, I will pioneer a new paradigm in the molecular engineering field called 'MechanoBodies' that will enable enhanced labelling and cargo delivery to cells under high shear stress.