Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021;6:1078–94. https://doi.org/10.1038/s41578-021-00358-0.
Hassett KJ, Benenato KE, Jacquinet E, Lee A, Woods A, Yuzhakov A, et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol Ther Nucleic Acids. 2019;15:1–11. https://doi.org/10.1016/j.omtn.2019.01.013.
Kang JS, DeLuca PP, Lee KC. Emerging PEGylated drugs. Expert Opin Emerg Drugs. 2009;14:363–80. https://doi.org/10.1517/14728210902907847.
Pasut G, Veronese FM. PEG conjugates in clinical development or use as anticancer agents: an overview. Adv Drug Deliv Rev. 2009;61:1177–88. https://doi.org/10.1016/j.addr.2009.02.010.
Knop K, Hoogenboom R, Fischer D, Schubert US. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed. 2010;49:6288–308. https://doi.org/10.1002/anie.200902672.
Shiaishi K. Considering the immunogenicity of PEG: strategies for overcoming issues with PEGylated nanomedicines. Nanomedicine. 2025. https://doi.org/10.1080/17435889.2025.2538423
Zhang P, Sun F, Liu S, Jiang S. Anti-PEG antibodies in the clinic: current issues and beyond PEGylation. J Control Release. 2016;244:184–93. https://doi.org/10.1016/j.jconrel.2016.06.040.
Verhoef JJF, Carpenter JF, Anchordoquy TJ, Schellekens H. Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics. Drug Discov Today. 2014;19:1945–52. https://doi.org/10.1016/j.drudis.2014.08.015.
Yang Q, Lai SK. Anti-PEG immunity: emergence, characteristics, and unaddressed questions. Nanomed Nanobiotechnol. 2015;7:655–77. https://doi.org/10.1002/wnan.1339.
Lubich C, Allacher P, de la Rosa M, Bauer A, Prenninger T, Horling FM, et al. The mystery of antibodies against polyethylene glycol (PEG): what do we know?. Pharm Res. 2016;33:2239–49. https://doi.org/10.1007/s11095-016-1961-x.
Schellekens H, Hennink WE, Brinks V. The immunogenicity of polyethylene glycol: facts and fiction. Pharm Res. 2013;30:1729–34. https://doi.org/10.1007/s11095-013-1067-7.
Ju Y, Lee WS, Pilkington E, Kelly HG, Li S, Selva KJ, et al. Anti-PEG antibodies boosted in humans by SARS-CoV-2 lipid nanoparticle mRNA vaccine. ACS Nano. 2022;16:11769–80. https://doi.org/10.1021/acsnano.2c04543.
Richter AW, Åkerblom E. Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polyethylene glycol modified allergens or placebo, and in healthy blood donors. Int Archs Allergy Appl Immun. 1984;74:36–39. https://doi.org/10.1159/000233512.
Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–23. https://doi.org/10.1517/17425247.2012.720969.
Chen BM, Su YC, Chang CJ, Burnouf PA, Chuang KH, Chen CH, et al. Measurement of pre-existing IgG and IgM antibodies against polyethylene glycol in healthy individuals. Anal Chem. 2016;888:10661–6. https://doi.org/10.1021/acs.analchem.6b03109.
Dams ETM, Laverman P, Oyen WJG, Storm G, Scherphof GL, van der Meer JWM, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharm Exp Ther. 2000;292:1071–9. https://doi.org/10.1016/S0022-3565(24)35391-1.
Laverman P, Carstens MG, Boerman OC, Dams ETM, Oyen WJG, van Roojien N, et al. Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharm Exp Ther. 2001;298:607–12. https://doi.org/10.1016/S0022-3565(24)29419-240.
Ishida T, Ichiahara M, Wang XY, Yamamoto K, Kimura J, Majima E, Kiwada H. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release. 2006;112:15–25. https://doi.org/10.1016/j.jconrel.2006.01.005.
Kozma GT, Mészáros T, Vashegyi I, Fülöp T, Örfi E, Dézsi L, et al. Pseudo-anaphylaxis to polyethylene glycol (PEG)-coated liposomes: roles of anti-PEG IgM and complement activation in a porcine model of human infusion reactions. ACS Nano. 2019;13:9315–24. https://doi.org/10.1021/acsnano.9b03942.
Zhou Z-H, Cortese MM, Fang J-L, Wood R, Hummell DS, Risma KA, et al. Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination. Vaccine. 2023;41:4183–9. https://doi.org/10.1016/j.vaccine.2023.05.029.
Kozma GT, Shimizu T, Ishida T, Szebeni J Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv Drug Deliv Rev. 154–5:163–75. https://doi.org/10.1016/j.addr.2020.07.024.
McSweeney MD, Mohan M, Commins S, Lai SK Anaphylaxis to Pfizer/ BioNTech mRNA COVID-19 vaccine in a patient with clinically confirmed PEG allergy. Front Allergy. 2021;2. https://doi.org/10.3389/falgy.2021.715844.
Liu YL, Liao TY, Ho KW, Liu ES, Huang BC, Hong ST, et al. Impact of pre-existing anti-polyethylene glycol antibodies on the pharmacokinetics and efficacy of a COVID-19 mRNA vaccine (Comirnaty) in vivo. Biomater Res. 2024;28:0112. https://doi.org/10.34133/bmr.0112.
Thi TTH, Pilkington EH, Nguyen DH, Lee JS, Park KD, Truong NP. The importance of poly (ethylene glycol) alternatives for overcoming PEG immunogenicity in drug delivery and bioconjugation. Polymers. 2020;12:298. https://doi.org/10.3390/polym12020298.
Zalipsky S, Hansen BH, Oaks JM, Allen TM. Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes. J Pharm Sci. 1986;85:133–7. https://doi.org/10.1021/js9504043.
Barz M, Luxenhofer R, Zentel R, Vicent MJ. Overcoming the PEG- addiction: well-defined alternatives to PEG, from structure–property relationships to better defined therapeutics. Polym Chem. 2011;2:1900–18. https://doi.org/10.1039/c0py00406e.
Kierstead PH, Okochi H, Venditto VJ, Chuong TC, Kivimae S, Fréchet JMJ, et al. The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes. J Control Release. 2015;213:1–9. https://doi.org/10.1016/j.jconrel.2015.06.023.
Estephan ZG, Schlenoff PS, Schlenoff JB. Zwitteration as an alternative to PEGylation. Langmuir. 2011;27:6794–6800. https://doi.org/10.1021/la200227b.
Li Q, Wen C, Yang J, Zhou X, Zhu Y, Zheng J, et al. Zwitterionic biomaterials. Chem Rev. 2022;122:17073–154. https://doi.org/10.1021/acs.chemrev.2c00344.
Zhang P, Sun F, Tsao C, Jiang S. Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity. Proc Natl Acad Sci USA. 2015;114:12046–51. https://doi.org/10.1073/pnas.1512465112.
Li B, Yuan Z, Hung HC, Ma J, Jain P, Tsao C, et al. Revealing the immunogenic risk of polymers. Angew Chem Int Ed. 2018;57:13873–6. https://doi.org/10.1002/anie.201808615.
Zaman R, Isalm RA, Ibnat N, Othman I, Zaini A, Lee CY, Chowdhury EH. Current strategies in extending half-lives of therapeutic proteins. J Control Release. 2019;301:176–89. https://doi.org/10.1016/j.jconrel.2019.02.016.
Rondon A, Mahri S, Morales-Yanez F, Dumoulin M, Vanbever R. Protein engineering strategies for improved pharmacokinetics. Adv Funct Mater. 2021;31:2101633. https://doi.org/10.1002/adfm.202101633.
Ryujin T, Shimizu T, Miyahara R, Asai D, Shimazui R, Yoshikawa T, et al. Blood retention and antigenicity of polycarboxybetaine-modified liposomes. Int J Pharm. 2020;586:119521. https://doi.org/10.1016/j.ijpharm.2020.119521.
Shiraishi K, Hamano M, Ma H, Kawano K, Maitani Y, Aoshi T, et al. Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon. J Control Release. 2013;165:183–90. https://doi.org/10.1016/j.jconrel.2012.11.016.
Ma H, Shiraishi K, Minowa T, Kawano K, Yokoyama M, Hattori Y, et al. Accelerated blood clearance was not induced for a gadolinium-containing PEG-poly(L-lysine)-based polymeric micelle in mice. Pharm Res. 2010;27:296–302. https://doi.org/10.1007/s11095-009-0018-9.
Shiraishi K, Yokoyama M. Antigenicity extension: a novel concept explained by the immunogenicity of PEG. ACS Bio Med Chem Au. 2025;5:42–54. https://doi.org/10.1021/acsbiomedchemau.4c00042.
Sherman MR, Williams LD, Sobczyk MA, Michaels SJ, Saifer MG. Role of the methoxy group in immune responses to mPEG-protein conjugates. Bioconjugate Chem. 2012;23:485–99. https://doi.org/10.1021/bc200551b.
Saifer MGP, Williams LD, Sobczyk MA, Michaels SJ, Sherman MR. Selectivity of binding of PEGs and PEG-like oligomers to anti-PEG antibodies induced by methoxyPEG-proteins. Mol Immunol. 2014;57:236–46. https://doi.org/10.1016/j.molimm.2013.07.014.
Shimizu T, Lila ASA, Fujita R, Awata M, Kawanishi M, Hashimoto Y, et al. A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes. Eur J Pharm Biopharm. 2018;127:142. https://doi.org/10.1016/j.ejpb.2018.02.019.
Shimizu T, Awata M, Lila ASA, Yoshioka C, Kawaguchi Y, Ando H, et al. Complement activation induced by PEG enhances humoral immune responses against antigens encapsulated in PEG-modified liposomes. J Control Release. 2021;329:1046–53. https://doi.org/10.1016/j.jconrel.2020.10.033.
Yamamoto T, Yokoyama M, Opanasopit P, Hayama A, Kawano K, Maitani Y. What are determining factors for stable drug incorporation into polymeric micelle carriers? Consideration on physical and chemical characters of the micelle inner core. J Controlled Release. 2007;123:11–18. https://doi.org/10.1016/j.jconrel.2007.07.008.
Shiraishi K, Kawano K, Maitani Y, Aoshi T, Ishii KJ, Sanada Y, et al. Exploring the relationship between anti-PEG IgM behaviors and PEGylated nanoparticles and its significance for accelerated blood clearance. J Control Release. 2016;234:59–67. https://doi.org/10.1016/j.jconrel.2016.05.010.
Dreier P, Matthes R, Fuß F, Schmidt J, Schulz D, Linden GM, et al. Isomerization of poly(ethylene glycol): a strategy for the evasion of anti-PEG antibody recognition. J Am Chem Soc. 2025;147:21538–21548. https://doi.org/10.1021/jacs.5c02716.
Sánchez-Cerrillo DM, Shiraishi K, Mallen-Huertas L, Peters R, Wilson DA, Neumann K. Introducing sulfur ylides as aharge-neutral termini for mitigating poly(ethylene glycol) antigenicity in nanomedicine. JACS Au. 2025;5:4378–88. https://doi.org/10.1021/jacsau.5c00748.


















Leave a Reply