Through targeted binding to the cell membrane, structural DNA nanotechnology has the potential to guide and affix biomolecules such as drugs, growth factors and nanobiosensors to the surfaces of cells....

DNA nanotechnology has proven exceptionally apt at probing and manipulating biological environments as it can create nanostructures of almost arbitrary shape that permit countless types of modifications, all while being inherently biocompatible. Emergent areas of particular interest are applications involving cellular membranes, but to fully explore the range of possibilities requires interdisciplinary knowledge of DNA nanotechnology, cell and membrane biology, and biophysics. In this review, we aim for a concise introduction to the intersection of these three fields. After briefly revisiting DNA nanotechnology, as well as the biological and mechanical properties of lipid bilayers and cellular membranes, we summarize strategies to mediate interactions between membranes and DNA nanostructures, with a focus on programmed delivery onto, into, and through lipid membranes. We also highlight emerging applications, including membrane sculpting, multicell self-assembly, spatial arrangement and organization of ligands and proteins, biomechanical sensing, synthetic DNA nanopores, biological imaging, and biomelecular sensing. Many critical but exciting challenges lie ahead, and we outline what strikes us as promising directions when translating DNA nanostructures for future in vitro and in vivo membrane applications.

Therapeutic and bioengineering applications of cells, such as cell printing and cell delivery, are directly limited by cell damage and death due to harsh mechanical conditions. Improved cellular robustness thus motivates investigations into cell encapsulation that provides essen- tial protection. Here we target the cell-surface glycocalyx and crosslink two layers of DNA origami nanorods on the cellular plasma membrane to form a nanoscale protective shell. This modular and programmable approach enables fine control over the layering and composition of membrane-deposited nanorods. We show that the DNA origami nanoshell modulates the biophysical properties of cell membranes by enhancing membrane stiffness and lowering lipid fluidity. Moreover, the nanoshell serves as armor, protecting cells, limiting swelling and ulti- mately improving their viability against mechanical stress from osmotic imbalance and cen- trifugal forces. Our results demonstrate the potential of the nanoshell, not only as a cellular protection strategy, but also as a platform for manipulating and studying plasma membrane mechanics.

The bioengineering applications of cells, such as cell printing and multicellular assembly, are directly limited by cell damage and death due to a harsh environment. Improved cellular robustness thus motivates investigations into cell encapsulation, which provides essential protection. Here we target the cell-surface glycocalyx and cross-link two layers of DNA nanorods on the cellular plasma membrane to form a modular and programmable nanoshell. We show that the DNA origami nanoshell modulates the biophysical properties of cell membranes by enhancing the membrane stiffness and lowering the lipid fluidity. The nanoshell also serves as armor to protect cells and improve their viability against mechanical stress from osmotic imbalance, centrifugal forces, and fluid shear stress. Moreover, it enables mediated cell–cell interactions for effective and robust multicellular assembly. Our results demonstrate the potential of the nanoshell, not only as a cellular protection strategy but also as a platform for cell and cell membrane manipulation.