Poly(sarcosine) Lipid Synthesis From CO ₂ ‐Based Sarcosine‐ <i>N</i> ‐Carboxyanhydride

Polymer lipids (PLs) are an essential component for the stability of lipid nanoparticles (LNPs) for gene delivery. Poly(ethylene glycol) (PEG)-based lipids are the current gold standard. However, they are suspected to be responsible for rare adverse reactions to the LNP-based COVID-19 vaccines. Therefore, alternative PLs are being intensively investigated. A particularly promising alternative are poly(sarcosine) (PSar)-based lipids. However, one significant bottleneck of pSar-based biomaterials is the synthesis of the monomer sarcosine-N-carboxyanhydride (Sar-NCA). Current methods rely on highly toxic di- or triphosgene to obtain the monomer directly from the amino acid sarcosine. Herein, we present a phosgene-free, CO₂-based route to Sar-NCA in gram scale and excellent purity, suitable for the subsequent living polymerization to pSar. Furthermore, we used the obtained pSar for the synthesis of pSar lipids suitable for LNP preparation. Due to its low toxicity and simplicity, the CO₂-based Sar-NCA synthesis has great potential to become an attractive alternative to current monomer synthesis pathways.