# Poly(sarcosine) Lipid Synthesis From CO2‐Based Sarcosine‐N‐Carboxyanhydride

## TL;DR

This paper introduces a safer, CO2-based method to make a key component for gene delivery lipids, offering a less toxic alternative to current methods.

## Contribution

A phosgene-free, CO2-based synthesis of Sar-NCA at gram scale with high purity is developed.

## Key findings

- The CO2-based Sar-NCA synthesis is scalable and produces high-purity monomers.
- The synthesized poly(sarcosine) can be used to make polymer lipids for lipid nanoparticles.
- The new method is less toxic and simpler than traditional phosgene-based approaches.

## Abstract

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.

In this work, we optimize and scale‐up a CO2‐based synthesis of sarcosine‐N‐carboxyanhydride (Sar‐NCA) to the gram scale. The low toxicity and simplicity of the approach make it an attractive alternative to current toxic phosgene‐based approaches. The CO2‐based Sar‐NCA has sufficient purity for controlled polymerization. The obtained poly(sarcosine)s can subsequently be used for the synthesis of polymer lipids suitable for lipid nanoparticles.