Lipid packing and cholesterol content regulate membrane wetting by biomolecular condensates

Biomolecular condensates play a pivotal role in cellular processes by interacting with membranes through wetting transitions, leading to mutual remodeling. We investigated how membrane composition, particularly lipid packing, affects condensate wetting using hyperspectral imaging and phasor analysis. Our results show that lipid packing, rather than phase state, determines condensate affinity for membranes. Increasing lipid chain length or cholesterol content enhances lipid packing, thereby decreasing condensate affinity. This regulatory mechanism is consistent across various condensate-membrane systems, underscoring the critical role of the membrane interface. Additionally, protein adsorption promotes extensive membrane remodeling, including tube and double-membrane sheet formation. This work provides a novel mechanism by which membrane composition fine-tunes condensate wetting, highlighting its potential impact on cellular functions and organelle interactions.