Tunable DNA-Stabilized Bicelles as Nanoscale Membrane Mimetic Systems.

Membrane proteins are central to cellular function and constitute the majority of drug targets, yet their structural and functional characterization at the single-molecule level requires stabilization within a native-like lipid environment. Here, we introduce a robust and tunable DNA origami nanodisc that incorporates inherently planar lipid bicelles as a promising platform for future membrane protein studies. The highly charged and bulky DNA envelope acts as a structural stabilizer, enabling efficient bicelle incorporation and stabilization. Moreover, bilayer geometry can be precisely tuned by adjusting the long-chain to short-chain lipid ratio (q-ratio), yielding diameters from ∼18 to 26 nm. As a proof of concept, we demonstrate the successful association of Fragaceatoxin C (FraC) monomers, a pore-forming membrane protein, with the DNA-stabilized bicelles. Potential applications of this versatile platform include high-throughput membrane protein analysis, hydrophobic drug delivery, and hybrid nanopore sensing.