Engineering Synthetic Erythrocytes as Next‐Generation Blood Substitutes

Abstract Blood scarcity is one of the main causes of healthcare disruptions worldwide, with blood shortages occurring at an alarming rate. Over the last decades, blood substitutes have aimed at reinforcing the supply of blood, with several products (e.g., hemoglobin (Hb)‐based oxygen (O₂) carriers, perfluorocarbons (PFC)) achieving a limited degree of success. Regardless, there is still no widespread solution to this problem due to persistent challenges in product safety and scalability. In this Review, different advances are described in the field of blood substitution, particularly in the development of artificial red blood cells, otherwise known as engineered erythrocytes (EE). The different strategies are categorized into natural, synthetic, or hybrid approaches, and discuss their potential in terms of safety and scalability. Synthetic EEs are identified as the most powerful approach, and describe erythrocytes from a materials engineering perspective. Their biological structure and function are reviewed, as well as explore different methods of assembling a material‐based cell. Specifically, it is discussed how to recreate size, shape, and deformability through particle fabrication, and how to recreate the functional machinery through synthetic biology and nanotechnology. It is concluded by describing the versatile nature of synthetic erythrocytes in medicine and pharmaceuticals and propose specific directions for the field of erythrocyte engineering.