Lipid nanoparticles (LNPs) have become the leading platform for delivering mRNA therapeutics, composed of four essential components: ionizable lipid, phospholipid, cholesterol, and a PEG-lipid. Among these, the ionizable lipid and PEG-lipid are synthetic and known contributors to immunogenicity and cytotoxicity, which can limit delivery efficiency and restrict repeated dosing. In this work, we introduce a zwitterionic materials-based strategy to modify these synthetic components within existing LNP architectures. By incorporating zwitterionic moieties into either the ionizable lipid or PEG-lipid replacements, we retain the structural integrity and delivery capacity of the LNP while significantly improving its biological profile. The zwitterionic-modified LNPs (Z-LNPs) demonstrated reduced cytokine induction and mitigated the accelerated blood clearance (ABC) effect typically associated with PEG-containing systems. Importantly, Z-LNPs achieved higher mRNA transfection efficiency and protein expression across multiple in vitro models and in vivo settings, including both intravenous and intramuscular administration routes. These results highlight the potential of zwitterionic modification as a modular approach to improve the safety and potency of LNP systems by directly targeting the immunogenic limitations of their synthetic components. This strategy provides a promising pathway toward more efficient, repeatable, and clinically translatable RNA delivery platforms.
