Blood is a precious and vital resource for many clinical interventions. Erythrocytes, its key component, are used to save thousands of lives every day worldwide. Yet, in low- and middle-income countries, its scarcity and unsafe control are endemic burdens that cost lives. In spite of several decades of attempts to develop a safe and universal blood substitute, this goal has yet to be achieved. Beyond the mere transport of gasses, erythrocytes have evolved together with their host organisms to perform very specialized functions. It is now clear that much of their complexity is indispensable to establish effective cardiovascular regulation. Yet, reproducing this complexity in a synthetic, functional facsimile is a challenging endeavour that requires new methods and multidisciplinary approaches. The ambitious goal of SynEry is to reproduce, in an advanced lipid vesicle, the following key features of erythrocytes: adequate lipid asymmetry with raft-like nanodomains; integration of essential functional proteins (both cytosolic and transmembrane) and a biomimetic cytoskeleton (conferring durability, flexibility and biconcavity); enhanced immune tolerability; responsivity to environmental cues (such as under deformation and hypoxia). These goals will be tackled by an interdisciplinary consortium bringing expertise on: droplet-based microfluidics combined with interfacial self-assembly of biofunctionalized nanoparticles (to build complex biomimetic membranes with ordered cytoskeletal nanodomains); DNA origami and self-assembling peptide technologies (to reconstruct a biomimetic cell cortex); and in-vivo testing models (to verify biocompatibility and functionality). The knowledge gained by producing a synthetic erythrocyte, is envisioned to enable the production of artificial cells with in-vivo applicability and it will pave the way towards the future development of an effective blood substitute that can remedy pervasive global blood availability and safety issues