RNA–Lipid Interactions

RNA and lipids are two of the most ancient classes of biomolecules, yet their direct interactions have been largely overlooked. Our work has established that lipid membranes can interact directly with RNA in a sequence-dependent manner, modulating RNA catalytic activity, stability, and localization. This emerging field has implications spanning the origin of life, synthetic biology, and modern cell regulation.

Sequence-Dependent RNA-Lipid Binding

We showed that RNA binds lipid membranes in a manner dependent on nucleotide content, base pairing state, and length (Czerniak & Sáenz, 2022, PNAS). Key determinants:

• Guanine content: short, guanine-rich single-stranded RNAs bind most effectively to zwitterionic phospholipid membranes.
• G-quadruplex structures: G-quadruplex formation further enhances membrane binding.
• Base pairing: double-stranded RNAs bind less effectively than single-stranded RNAs.
• Length: longer RNAs show stronger relative binding.

These interactions occur with common zwitterionic phospholipids (e.g., DOPC), indicating they are not purely electrostatic.

Membrane Modulation of Ribozyme Activity

Lipid membranes affect RNA catalysis in ribozyme-specific and membrane-phase-dependent ways:

• R3C ligase ribozyme: membrane presence reduces activity by sequestering substrate RNA. Engineering the substrate to enhance membrane binding creates a lipid-sensitive ribozyme with riboswitch-like behavior (Czerniak & Sáenz, 2022, PNAS).
• HDV ribozyme: gel-phase membranes decrease self-cleavage activity (Czerniak & Sáenz, 2025, Biology of the Cell).
• Hammerhead ribozyme: gel-phase membranes increase activity — the opposite effect to HDV (Czerniak & Sáenz, 2025, Biology of the Cell).
• RNA stability: liquid-phase membranes promote RNA degradation, preferentially in single-stranded regions.

RNA World Implications

If RNA and lipids can interact directly and functionally, lipid membranes could have served as organizational scaffolds for primordial RNA systems — concentrating, protecting, and regulating RNA before protein-based regulation evolved. Lipid-stabilized prebiotic foams with thermal gradients can accumulate and oligomerize RNA (Tekin et al., 2022, ChemBioChem).

The question posed in our review: could there be life with only RNA and lipids? (Czerniak & Sáenz, 2025, RNA Biology)

Applications

• Synthetic riboswitches: RNA sequences engineered to respond to membrane presence or composition
• RNA-based lipid biosensors: RNAs that report on membrane state
• RNA therapeutics: understanding RNA-lipid interactions improves lipid nanoparticle delivery of mRNA vaccines
• Synthetic cells: RNA-lipid interactions as an orthogonal regulatory layer for minimal synthetic systems