Stable, micron-scale lipocondensates achieving prolonged circulation without PEGlyated lipids

Biomolecular condensates are key organizers of cellular biochemistry and are emerging as promising platforms for therapeutic delivery. However, how their molecular composition influences lipid organization and interfacial behavior remains poorly understood. Here, we report lipid-containing condensates ("LipCons") that form stable, micron-scale assemblies exhibiting distinctive lipid organization and excellent biocompatibility in circulation. LipCon structures reach cell-like dimensions (∼3 µm diameter), far bigger than conventional liposomes. Functionally, LipCons composed solely of natural lipids display prolonged circulation, achieving an initial half-life of ∼13 hours-over 10× longer than the most structurally comparable lipid-coated condensate system reported to date and rivaling nano-scale PEGylated systems. In fact, at micron-scale, liposomes including PEGylated ones, are very unstable. Small-angle X-ray scattering (SAXS) and fluorescence recovery after photobleaching (FRAP) reveal that the lipid layer at the condensate surface has a rather unusual structure, showing reduced lipid mobility and unique interfacial packing. This PEG-free stability, combined with tunable composition and biocompatibility, establishes LipCons as a versatile platform for sustained systemic delivery and synthetic biology applications.