Lipid tail chemistry regulates selective membrane interactions with model DNA nanoprobes and DNA-based coacervates

Abstract

Biological membranes actively regulate their composition to fine-tune their packing, fluidity, phase and surface charge, key properties that influence biomolecular interactions driving essential cellular pathways. While membrane surface charge is often attributed to specific lipid headgroups, the role of acyl-chain chemistry in modulating the interplay between these biophysical membrane properties remains unexplored. Here, we systematically investigate how acyl-chain length and saturation modulate lipid packing, fluidity, and membrane surface charge in zwitterionic lipid membranes. Using amphiphilic DNA nanoprobes as model charged biomolecules, we describe the interplay between packing, fluidity, phase and charge, identifying a packing-dependent guiding principle for membrane interactions that persists in the presence of anionic lipids. We also demonstrate that the identity and hydrophobicity of membrane anchors in nanoprobes significantly influence their binding to membranes. By integrating acyl-chain chemistry and membrane biophysical properties into design criteria for biomolecular attachment, our findings provide a mechanistic framework for engineering membrane interactions with both DNA nanoprobes and DNA-based coacervates. Beyond direct application to biomimetic platforms and synthetic cell engineering, these insights are relevant to lipid-based vaccine nanotechnologies and a fundamental understanding of membrane-biomolecule interactions in living cells.