The secret life of RNA and lipids

Czerniak, T.; Sáenz, J. P. (2025) RNA Biology, 22(1), 1–28. DOI: 10.1080/15476286.2025.2526903

Summary

This review synthesizes the emerging field of RNA-lipid interactions, encompassing the chemical basis for these interactions and their implications for synthetic biology, RNA World scenarios, and modern cell biology. We discuss how RNA can selectively bind lipid membranes in a sequence-dependent manner — an observation first reported by our group (Czerniak & Sáenz, 2022, PNAS) — and how these interactions might be exploited to engineer RNA-based sensors and regulatory elements. The review poses the provocative question: could there be life with only RNA and lipids?

Key Findings

• Chemical basis of RNA-lipid interactions: guanine-rich sequences and G-quadruplex structures promote lipid binding; interactions occur with zwitterionic membranes, not only charged lipids.
• Implications for RNA World: lipid membranes could have served as organizational scaffolds for primordial RNA systems — concentrating, protecting, and regulating RNA before protein-based regulation evolved.
• Synthetic biology applications: RNA-lipid interactions enable the design of membrane-sensitive riboswitches, RNA-based lipid biosensors, and orthogonal regulatory systems for synthetic cells.
• Modern cell biology: the possibility that undiscovered RNA-membrane interactions play regulatory roles in contemporary cells.
• RNA therapeutics: insights into RNA-lipid interactions are relevant to lipid nanoparticle-based mRNA vaccine delivery.

Significance

This review established the conceptual framework for a new subdiscipline at the intersection of RNA biology and membrane biophysics. By articulating the vision of RNA-lipid interactions as a general biological principle — spanning from the origin of life to synthetic biology to modern regulation — it positioned the lab’s work at the frontier of an emerging field.