• • C18-POx-LNPs achieved over 200-fold higher transfection efficiency than PEG-LNPs in mice with pre-existing anti-PEG antibodies, directly addressing the clinical bottleneck of reduced efficacy in PEG-sensitized populations.
• • Single-tailed C18-POx conjugates produced LNPs with smaller particle sizes and superior freeze-thaw stability compared to other POx variants, indicating enhanced colloidal stability for storage and handling.
• • C18-POx-LNPs fully replacing DMG-PEG maintained comparable in vivo transfection efficiency to PEG-LNPs in naive mice, demonstrating non-inferior performance without PEG.
• • Repeated POx-LNP administration elicited dose-dependent anti-POx IgM and IgG responses, with antibody titers inversely correlated with POx hydrophilicity (PEtOx > PMeOx), highlighting the need to balance stealth and immunogenicity.