Membrane and glycocalyx tethering of DNA nanostructures for enhanced uptake

DNA nanostructures (DNs) have been increasingly utilized in biosensing, drug delivery, diagnostics and therapeutics, because of their programmable assembly, control over size and shape, and ease of functionalization. However, the low cellular uptake of DNs has limited their effectiveness in these biomedical applications. Here we demonstrate the potential of membrane and glycocalyx binding as general strategies to enhance the cellular uptake of DNs. By targeting the plasma membrane and cell-surface glycocalyx, the uptake of all three distinct DNs is significantly enhanced as compared to uptake of bare DNs. We also demonstrate the viability of single-step membrane labeling by cholesterol-DNs as competitive with previous multistep approaches. Further, we show that the endocytic pathway of membrane-bound DNs is an interdependent process that involves scavenger receptors, clathrin-, and caveolinmediated endocytosis. Our findings may potentially expand the toolbox for effective cellular delivery of DNA nanostructured systems.