Programmable Zwitterionic Droplets as Biomolecular Sorters and Model of Membraneless Organelles Suiying Ye , Umberto Capasso Palmiero, Carolina Paganini, Marie R. G. Kopp, Miriam Linsenmeier, Andreas M. Küffner, Paolo Arosio Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland Growing evidence suggests that the biochemical processes in cells can be regulated in time and space through the formation of membraneless organelles (MLO) via liquid-liquid phase separation (LLPS). Several scaffold components have been found to form these biomolecular condensates, including associative disordered proteins containing low-complexity domains (LCDs). These protein LCDs encode multivalent interactions that modulate different mesoscopic properties of the compartments. It would be attractive to develop model polymeric systems capable to mimic this behavior and independently control different properties of coacervates. In this work, we present programmable coacervates based on responsive zwitterionic polymers encoding various intermolecular associations. Beginning with a reference polymer that remarkably excludes most molecules, a range of diverse functional groups were progressively added to introduce an increasing number of different intermolecular interactions. This strategy enabled precise control over multiple emerging properties of the coacervates, including stimulus-responsiveness, polarity, selective uptake of client molecules, fusion times, and miscibility. By exploiting this high programmability, a model of cellular compartmentalization was reproduced, wherein the coacervates without physical barriers were capable of confining different molecules in space. Moreover, these biomolecular sorters were demonstrated to effectively localize, segregate, and enable the detection of target molecules even within complex mixtures, opening attractive applications in bioseparation, and diagnostics. Acknowledgment: Swiss National Science Foundation (Grant No. 205321-17905), the Synapsis Foundation for Alzheimer’s disease (Zurich). References 1. 1. Umberto Capasso Palmiero, Carolina Paganini, Marie R. G. Kopp, Miriam Linsenmeier, Andreas M. Küffner, and Paolo 2. Arosio. Programmable zwitterionic droplets as biomolecular sorters and model of membraneless organelles. Advanced 3. Materials, 34(4):2104837, 2022. 4. 2. Carolina Paganini, Umberto Capasso Palmiero, Sabrina Picciotto, Alessandro Molinelli, Ilaria Porello, Giorgia Adamo, 5. Mauro Manno, Antonella Bongiovanni, and Paolo Arosio. High-yield separation of extracellular vesicles using programmable 6. zwitterionic coacervates. Small, 19(1):2204736, 2023.
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