The PEG Dilemma in Lipid Nanoparticles.

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.