Zwitterionic PEGylation of Nanodrugs for Reduced Immunogenicity and Improved Drug Delivery Efficacy

PEGylated liposomes are widely used as drug delivery carriers due to their prolonged circulation and enhanced accumulation at pathological sites. However, repeated administration can trigger the accelerated blood clearance (ABC) phenomenon, reducing delivery efficacy. Herein, we report a zwitterionic PEGylation strategy by grafting glutamic acid-lysine (EK) peptides onto PEGylated phospholipid derivatives to assemble liposome (Lip)-based drug delivery systems. Small-angle neutron scattering analysis confirmed that EK modification significantly enhanced Lip hydration, leading to a 40-fold reduction in protein adsorption compared to conventional PEGylation, which therefore reduced immune cell uptake, anti-PEG antibody production, and nonspecific hepatic accumulation of EK-Lip. Furthermore, even in the presence of preexisting APAs, EK-Lip could mitigate the ABC effect and exhibit a twofold increase in the area under the curve of the pharmacokinetic profile after multiple injections compared to Lip. When loaded with doxorubicin, the zwitterionic EK-Lip demonstrated lower immunogenicity and superior antitumor efficacy compared to conventional formulations. This work provides a facile strategy to assemble zwitterionic liposomes with modified surface chemistry, offering a promising solution to the ABC effect in PEGylated liposomes.