Abstract
<jats:p>The emergence of cellular life required co-existence of genetic molecules and compartments housing them1. However, the biological origin of robust membrane compartments is an enduring unsolved problem: the aqueous synthesis of amphiphilic diesters, such as glycerophospholipids, from polar diols without enzymes or organic cosolvents has never been achieved. Here, we demonstrate that nucleotides exhibit remarkable predisposed reactivity that overcomes this barrier. Unlike glycerol phosphates, nucleotides undergo selective, high-dilution lipidation in water to form phosphonucleolipids. We characterise the spontaneous self-assembly, during the reaction, of stable, cell-like vesicles that encapsulate small molecules. A survey of lipidation reactions points to the unique reactivity of the nucleotide diol as a critical component in nonenzymatic diester lipid synthesis. Our findings establish a direct chemical link between the components of the RNA2 and Lipid3 Worlds, suggesting that protocells were assembled from the very molecules enabling them to carry genetic information: nucleotides.</jats:p>