Alleviating immunogenicity of lipid-based vehicles via zwitterionic peptides surface functionalization for enhanced drug delivery performance

Lipid nanoparticles (LNPs) are widely used as highly efficient delivery vehicles for mRNA therapeutics, yet their repeated administration is frequently hindered by poly(ethylene glycol) (PEG)-related immunogenicity. PEGylated LNPs can trigger the production of anti-PEG antibodies (APA), which results in immune-mediated sequestration and elevated hepatic accumulation, ultimately undermining therapeutic efficacy. In this work, we developed low-immunogenic LNPs, designated as EK-LNPs, by modifying PEGylated phospholipid derivatives with the zwitterionic peptide featuring the sequence EKEKEKEC. EK-LNPs can significantly reduce their internalization by macrophages and other immune cells, suppress the generation of anti-PEG IgM and IgG, and thereby mitigate mononuclear phagocyte system-mediated clearance and nonspecific hepatic accumulation. Furthermore, following repeated-administration in a tumor model, conventional LNPs elicited APA-mediated immune responses that impaired the efficacy of subsequent PEGylated therapeutics. Whereas EK-LNPs effectively lowered their immunogenicity and enhanced the antitumor performance of subsequent EK-modified liposomal nanodrugs. This study presents a zwitterionic functionalization strategy for engineering lipid-based delivery platforms, which holds great promise for alleviating the immunogenicity of PEGylated delivery systems and improving overall drug delivery efficacy.