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This Perspective reframes the PEG dilemma not as a binary materials choice but as a surface\u2010engineering problem defined by measurable interfacial variables. We summarize PEG\u2010centric design levers, including chain length, terminal chemistry, PEG fraction, and mixed\u2010length 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\u2010molar\u2010mass PEG\u2010lipids and topology control. Such approaches may narrow epitope heterogeneity and clarify structure\u2010function relationships across key interfacial properties, including surface density and spacing, dissociation and exchange kinetics, and epitope persistence. Improved molecular definition will not eliminate PEG\u2010directed immunity in every setting, but it can improve predictability and manufacturing reproducibility, and may broaden the accessible design space for repeat\u2010dosing mRNA therapeutics. Finally, we discuss how interface design can be paired with immune\u2010aware dosing and monitoring strategies to support durable clinical efficacy and safety.<\/jats:p>","DOI":"10.1002\/smtd.202600004","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T10:33:19Z","timestamp":1773916399000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The PEG Dilemma in Lipid Nanoparticles"],"prefix":"10.1002","volume":"10","author":[{"given":"Minglong","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Precision and Intelligent Chemistry Department of Polymer Science and Engineering School of Chemistry and Materials Science University of Science and Technology of China  Hefei Anhui 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