Stable Synthetic Organelles from Aqueous Two-Phase Systems with Access to the Cell Translation Machinery

Cells compartmentalize vital processes in membrane-less organelles to gain spatiotemporal control of metabolism, signaling, and for protection under stress. While such compartments can be manipulated or even de novo designed with genetic engineering of cells, the transfer and operation of exogenous synthetic compartments for intracellular engineering is challenged by developing pathways for implantation into the cell, stability issues, toxicity, ability to maintain compartmentalization, and access to cellular machinery. Here we introduce dextran-lipid droplets as versatile exogenous synthetic compartments, that are readily uptaken by model cancer and immune cells and are stable inside cells for days. Furthermore, the droplets can encapsulate nucleic acids with high efficiency, are non-toxic and endosomal escape occurs when formulated with ionizable lipids, as shown by reporter protein translation of an mRNA hosted inside the organelles. We propose that such synthetic microreactors implanted into the cells will become an important bioengineering tool to incorporate more complex and bioorthogonal molecular systems into cells.