In eukaryotic cells, membraneless organelles reorganize through regulated interactions with the plasma membrane and its underlying cortex, where cytoskeletal coupling and inner-leaflet biochemistry tune condensate positioning, wetting, and function. Recreating such adaptive, cortex-mediated control in synthetic systems remains a challenge, requiring a chassis that combines interfacial programmability with the mechanical resilience necessary to withstand the osmotic and electrostatic stresses of bottom-up assembly. Here, we introduce polysaccharidosomes (P-somes); semipermeable, mechanically robust protocells that function as membrane-programmable chassis for directing coacervate-membrane coupling. By establishing a thin, cortex-like protein layer on the inner membrane leaflet via template-directed assembly, we demonstrate that in situ protein succinylation enables precise tuning of surface charge and coacervate-membrane wetting. Together with the systematic variation of membrane building blocks, this platform allows for fine control over coacervate wetting, morphology, and spatial organization. The uptake of external DNA adds a second tier of regulation: on nonpassivated membranes, DNA-reconfigured coacervates generate interfacial protrusions that bridge neighboring P-somes to promote tissue-like clustering, whereas on passivated membranes, they coalesce into a single, nonwetting, nucleus-like droplet centered within the lumen. This membrane-cortex-inspired framework integrates mechanical resilience with chemical programmability, providing a scalable route to constructing membranized protocells with self-organizing interiors and emergent collective behaviors.
Mukwaya et al. (Sun,) studied this question.