Visible Light Conjugation with Triazolinediones as a Route to Degradable Poly(ethylene glycol)–Lipids for mRNA Lipid Nanoparticle Formulation

Abstract Polyethylene glycol (PEG) is considered as the gold standard for colloidal stabilization of nanomedicines, yet PEG is non‐degradable and lacks functionality on the backbone. Herein, we introduce concomitantly PEG backbone functionality and degradability via a one‐step modification with 1,2,4‐triazoline‐3,5‐diones (TAD) under green light. The TAD‐PEG conjugates are degradable in aqueous medium under physiological conditions, with the rate of hydrolysis depending on pH and temperature. Subsequently, a PEG‐lipid is modified with TAD‐derivatives and successfully used for messenger RNA (mRNA) lipid nanoparticle (LNP) delivery, thereby improving mRNA transfection efficiency on multiple cell cultures in vitro. In vivo, in mice, mRNA LNP formulation exhibited a similar tissue distribution as common LNPs, with a slight decrease in transfection efficiency. Our findings pave the road towards the design of degradable, backbone‐functionalized PEG for applications in nanomedicine and beyond.