---
title: "Zwitterionic PEGylation (EK) for Liposomes to Reduce Immunogenicity and Improve Delivery"
id: "pubmed-42680140"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42680140"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42680140/"
doi: "10.1021/acsami.6c12129"
published_at: "2026-09-09T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Zwitterionic PEGylation (EK) for Liposomes to Reduce Immunogenicity and Improve Delivery
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42680140
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42680140/)
- **DOI:** [10.1021/acsami.6c12129](https://doi.org/10.1021%2Facsami.6c12129)
- **Published At:** 2026-09-09T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study reports a **zwitterionic PEGylation** approach that grafts glutamic acid-lysine (EK) peptides onto PEGylated phospholipid derivatives to create zwitterionic liposomes (EK-Lip). - Small-angle neutron scattering showed that EK modification increased liposome hydration compared with conventional PEGylation. - EK-Lip exhibited a roughly **40-fold reduction in protein adsorption** relative to conventional PEGylated liposomes. - Reduced protein adsorption correlated with decreased immune cell uptake, lower production of **anti-PEG antibodies (APAs)**, and reduced nonspecific hepatic accumulation of EK-Lip. - EK-Lip mitigated the **accelerated blood clearance (ABC)** phenomenon associated with repeated PEGylated liposome administration; even with preexisting APAs, EK-Lip showed improved behavior. - After multiple injections, EK-Lip produced an approximately **twofold increase in area under the curve (AUC)** of the pharmacokinetic profile versus conventional PEGylated liposomes. - When loaded with **doxorubicin**, EK-Lip demonstrated lower immunogenicity and superior antitumor efficacy compared with conventional formulations. - The work proposes a facile surface-chemistry modification strategy for liposomal drug carriers to address APA-mediated ABC and improve delivery efficacy.
## Clinical Analysis & Structured Key Points
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more resources ](https://pubmed.ncbi.nlm.nih.gov/42680140/#linkout) Title & authors Abstract Similar articles MeSH terms Substances Related information Grants and funding LinkOut - more resources ACS Appl Mater Interfaces Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22ACS+Appl+Mater+Interfaces%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22ACS+Appl+Mater+Interfaces%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42680140/) . 2026 Sep 9;18(35):47450-47460. doi: 10.1021/acsami.6c12129. # Zwitterionic PEGylation of Nanodrugs for Reduced Immunogenicity and Improved Drug Delivery Efficacy [Ning Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+N&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-2 "Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China."), [Zhiliang Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Z&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Mengqi Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Kangcheng Shen](https://pubmed.ncbi.nlm.nih.gov/?term=Shen+K&cauthor_id=42680140)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-3 "Biological Physics Group, Department of Physics and Astronomy, School of Natural Sciences, University of Manchester, Oxford Road, ManchesterM13 9PL, UK."), [Yubin Ke](https://pubmed.ncbi.nlm.nih.gov/?term=Ke+Y&cauthor_id=42680140)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-4 "Dongguan Neutron Science Center, Institute of High Energy Physics, Chinese Academy of Sciences, Dongguan, Guangdong523808, China."), [Mengqi Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+M&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jianhua Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42680140)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-2 "Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China."), [Xuzhi Hu](https://pubmed.ncbi.nlm.nih.gov/?term=Hu+X&cauthor_id=42680140)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-5 "State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, Gansu730000, China."), [Peiyu Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jingcheng Hao](https://pubmed.ncbi.nlm.nih.gov/?term=Hao+J&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jiwei Cui](https://pubmed.ncbi.nlm.nih.gov/?term=Cui+J&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#full-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China.") Affiliations Expand ### Affiliations * 1 Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China. * 2 Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China. * 3 Biological Physics Group, Department of Physics and Astronomy, School of Natural Sciences, University of Manchester, Oxford Road, ManchesterM13 9PL, UK. * 4 Dongguan Neutron Science Center, Institute of High Energy Physics, Chinese Academy of Sciences, Dongguan, Guangdong523808, China. * 5 State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, Gansu730000, China. * PMID: **42680140** * DOI: [ 10.1021/acsami.6c12129 ](https://doi.org/10.1021/acsami.6c12129) Item in Clipboard # Zwitterionic PEGylation of Nanodrugs for Reduced Immunogenicity and Improved Drug Delivery Efficacy Ning Wang et al. ACS Appl Mater Interfaces. 2026. Show details Display options Display options Format Abstract PubMed PMID ACS Appl Mater Interfaces Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22ACS+Appl+Mater+Interfaces%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22ACS+Appl+Mater+Interfaces%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42680140/) . 2026 Sep 9;18(35):47450-47460. doi: 10.1021/acsami.6c12129. ### Authors [Ning Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+N&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-2 "Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China."), [Zhiliang Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Z&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Mengqi Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Kangcheng Shen](https://pubmed.ncbi.nlm.nih.gov/?term=Shen+K&cauthor_id=42680140)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-3 "Biological Physics Group, Department of Physics and Astronomy, School of Natural Sciences, University of Manchester, Oxford Road, ManchesterM13 9PL, UK."), [Yubin Ke](https://pubmed.ncbi.nlm.nih.gov/?term=Ke+Y&cauthor_id=42680140)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-4 "Dongguan Neutron Science Center, Institute of High Energy Physics, Chinese Academy of Sciences, Dongguan, Guangdong523808, China."), [Mengqi Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+M&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jianhua Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42680140)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-2 "Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China."), [Xuzhi Hu](https://pubmed.ncbi.nlm.nih.gov/?term=Hu+X&cauthor_id=42680140)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-5 "State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, Gansu730000, China."), [Peiyu Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jingcheng Hao](https://pubmed.ncbi.nlm.nih.gov/?term=Hao+J&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China."), [Jiwei Cui](https://pubmed.ncbi.nlm.nih.gov/?term=Cui+J&cauthor_id=42680140)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42680140/#short-view-affiliation-1 "Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China.") ### Affiliations * 1 Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, and the School of Biomedical Engineering, Shandong University, Jinan, Shandong250100, China. * 2 Shandong Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong250012, China. * 3 Biological Physics Group, Department of Physics and Astronomy, School of Natural Sciences, University of Manchester, Oxford Road, ManchesterM13 9PL, UK. * 4 Dongguan Neutron Science Center, Institute of High Energy Physics, Chinese Academy of Sciences, Dongguan, Guangdong523808, China. * 5 State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, Gansu730000, China. * PMID: **42680140** * DOI: [ 10.1021/acsami.6c12129 ](https://doi.org/10.1021/acsami.6c12129) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract 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. **Keywords:** accelerated blood clearance; anti-PEG antibodies; liposomes; poly(ethylene glycol); zwitterionic modification. © 2026 American Chemical Society. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ Impact of Anti-PEG IgM Induced via the Topical Application of a Cosmetic Product Containing PEG Derivatives on the Antitumor Effects of PEGylated Liposomal Antitumor Drug Formulations in Mice. ](https://pubmed.ncbi.nlm.nih.gov/38273445/) Gaballa SA, Shimizu T, Takata H, Ando H, Ibrahim M, Emam SE, Amorim Matsuo NC, Kim Y, Naguib YW, Mady FM, Khaled KA, Ishida T.Gaballa SA, et al.Mol Pharm. 2024 Feb 5;21(2):622-632. doi: 10.1021/acs.molpharmaceut.3c00774. Epub 2024 Jan 25.Mol Pharm. 2024.PMID: 38273445 * [ A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes. ](https://pubmed.ncbi.nlm.nih.gov/29462689/) Shimizu T, Abu Lila AS, Fujita R, Awata M, Kawanishi M, Hashimoto Y, Okuhira K, Ishima Y, Ishi
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