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Over the last decades, blood substitutes have aimed at reinforcing the supply of blood, with several products (e.g., hemoglobin (Hb)\u2010based oxygen (O<jats:sub>2<\/jats:sub>) 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\u2010based 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.<\/jats:p>","DOI":"10.1002\/adfm.202315879","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T22:40:16Z","timestamp":1707432016000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Engineering Synthetic Erythrocytes as Next\u2010Generation Blood Substitutes"],"prefix":"10.1002","volume":"34","author":[{"given":"Francisca L.","family":"Gomes","sequence":"first","affiliation":[{"name":"Department of Molecules and Materials Laboratory of Biointerface Chemistry Faculty of Science and Technology Technical Medical Centre and MESA+ Institute University of Twente  Drienerlolaan 5 Enschede 7522NB The Netherlands"},{"name":"Department of Developmental BioEngineering Leijten Laboratory Faculty of Science and Technology Technical Medical Centre University of Twente  Drienerlolaan 5 Enschede 7522NB The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seol\u2010Ha","family":"Jeong","sequence":"additional","affiliation":[{"name":"Division of Engineering in Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School  65 Landsdowne Street Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Ryon","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Engineering in Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School  65 Landsdowne Street Cambridge MA 02139 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Leijten","sequence":"additional","affiliation":[{"name":"Department of Developmental BioEngineering Leijten Laboratory Faculty of Science and Technology Technical Medical Centre University of Twente  Drienerlolaan 5 Enschede 7522NB The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-0049","authenticated-orcid":false,"given":"Pascal","family":"Jonkheijm","sequence":"additional","affiliation":[{"name":"Department of Molecules and Materials Laboratory of Biointerface Chemistry Faculty of Science and Technology Technical Medical Centre and MESA+ Institute University of Twente  Drienerlolaan 5 Enschede 7522NB The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"W. 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