The PEG Dilemma in Lipid Nanoparticles

ABSTRACT Poly(ethylene glycol) lipids (PEG‐lipids) are widely used to stabilize mRNA lipid nanoparticles, yet repeat dosing can reveal delivery trade‐offs and immune liabilities arising from limited molecular definition at the nano‐bio interface. This Perspective reframes the PEG dilemma not as a binary materials choice but as a surface‐engineering problem defined by measurable interfacial variables. We summarize PEG‐centric design levers, including chain length, terminal chemistry, PEG fraction, and mixed‐length designs, and discuss recent progress in PEG alternatives alongside key translational constraints. A complementary strategy is to increase the molecular definition of PEG interfaces through discrete‐molar‐mass PEG‐lipids and topology control. Such approaches may narrow epitope heterogeneity and clarify structure‐function relationships across key interfacial properties, including surface density and spacing, dissociation and exchange kinetics, and epitope persistence. Improved molecular definition will not eliminate PEG‐directed immunity in every setting, but it can improve predictability and manufacturing reproducibility, and may broaden the accessible design space for repeat‐dosing mRNA therapeutics. Finally, we discuss how interface design can be paired with immune‐aware dosing and monitoring strategies to support durable clinical efficacy and safety.