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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.<\/jats:p>","DOI":"10.1021\/acsami.6c12129","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:13:27Z","timestamp":1788304407000},"page":"47450-47460","source":"Crossref","is-referenced-by-count":1,"title":["Zwitterionic PEGylation of Nanodrugs for Reduced Immunogenicity and Improved Drug Delivery Efficacy"],"prefix":"10.1021","volume":"18","author":[{"given":"Ning","family":"Wang","sequence":"first","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]},{"name":"School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University , , , ,","place":["Jinan, Shandong, China, 250012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Gao","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangcheng","family":"Shen","sequence":"additional","affiliation":[{"name":"University of Manchester , , Oxford Road , ,","place":["Manchester, UK, M13 9PL"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Ke","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , , ,","place":["Dongguan, Guangdong, China, 523808"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5227-8627","authenticated-orcid":true,"given":"Jianhua","family":"Li","sequence":"additional","affiliation":[{"name":"School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University , , , ,","place":["Jinan, Shandong, China, 250012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9246-7040","authenticated-orcid":true,"given":"Xuzhi","family":"Hu","sequence":"additional","affiliation":[{"name":"Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences , , , ,","place":["Lanzhou, Gansu, China, 730000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1715-5012","authenticated-orcid":true,"given":"Peiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9760-9677","authenticated-orcid":true,"given":"Jingcheng","family":"Hao","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1018-4336","authenticated-orcid":true,"given":"Jiwei","family":"Cui","sequence":"additional","affiliation":[{"name":"Shandong University , , , ,","place":["Jinan, Shandong, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"43","key":"2026091612070457200_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202401990","article-title":"A Review: Surface Engineering of Lipid-Based Drug Delivery Systems","volume":"20","author":"Patel","year":"2024","journal-title":"Small"},{"issue":"26","key":"2026091612070457200_cit2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202503631","article-title":"Photogenetic-Like Liposomes Disrupt Neuroligin-3 Dependency to Enhance Glioma Treatment","volume":"37","author":"Ding","year":"2025","journal-title":"Adv. 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