Electron‐Deficient Alkyne Lipids Enable Efficient Synthesis of Comparable Polymer Lipids via Copper‐Free Azide‐Alkyne Cycloaddition

Abstract Polymer lipids (PLs) are essential components of liposomes and lipid nanoparticles (LNPs) for drug and gene delivery, providing colloidal stabilization and defining the biological interface. While poly(ethylene glycol) (PEG)‐based PLs are the current standard, they are suspected to be responsible for rare adverse reactions, e. g. to LNP‐based Covid‐19 vaccines. Therefore, PLs based on alternative stealth polymers are being intensively investigated for their use in LNPs. However, alternative PLs often lack comparability due to different synthesis protocols and are often not easily accessible. Herein we present a catalyst‐free, efficient and versatile coupling procedure for PL synthesis based on azide‐functionalized polymers and electron‐deficient acetylene dicarboxylate lipids. To highlight the versatility of this approach, we prepared PLs based on PEG and 4 alternative stealth polymers with quantitative coupling efficiencies. The linker structure showed appropriate pH stability and biocompatibility. All PLs enabled the preparation of well‐defined liposomes with excellent stability. Our facile and versatile approach yields comparable PLs with minimized linker size, making them promising candidates for future comparative studies, and biomedical applications.