{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:32:21Z","timestamp":1792017141831,"version":"4.4.0"},"reference-count":120,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination with mRNA-LNP vaccines. Meanwhile, the US Food and Drug Administration (FDA) has added four black-box warnings in the instructions for mRNA-LNP vaccines. Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety. This review summarizes the experience of using mRNA-LNP vaccines from the mechanism of the anti-PEG antibodies generation, detection methods, clinical failure cases of PEG-containing products, harm analysis of abuse of PEGylation, and alternatives. In light of the increasing prevalence of anti-PEG antibodies in the population and the need to avoid secondary injuries, this review article holds greater significance by offering insights for drug developers. It suggests avoiding the use of PEG excipients when designing PEGylated drugs or PEG-modified nano-formulations and provides references for strategies such as utilizing PEG-free or alternative excipients.<\/jats:p>","DOI":"10.3390\/pharmaceutics17060798","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T08:43:58Z","timestamp":1750322638000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Implications of Anaphylaxis Following mRNA-LNP Vaccines: It Is Urgent to Eliminate PEG and Find Alternatives"],"prefix":"10.3390","volume":"17","author":[{"given":"Jinxing","family":"Song","sequence":"first","affiliation":[{"name":"WuXi Biologics, 190 Hedan Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dihan","family":"Su","sequence":"additional","affiliation":[{"name":"WuXi Biologics, 190 Hedan Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9179-2709","authenticated-orcid":false,"given":"Hongbing","family":"Wu","sequence":"additional","affiliation":[{"name":"WuXi Biologics, 190 Hedan Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Guo","sequence":"additional","affiliation":[{"name":"WuXi Biologics, 190 Hedan Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1080\/10408363.2020.1783198","article-title":"The COVID-19 pandemic","volume":"57","author":"Ciotti","year":"2020","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.anai.2021.10.022","article-title":"The COVID-19 pandemic adverse effects on the social determinants of health in children and families","volume":"128","author":"Abrams","year":"2022","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41418-020-00720-9","article-title":"COVID-19 vaccines: Where we stand and challenges ahead","volume":"28","author":"Forni","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/d41573-020-00073-5","article-title":"The COVID-19 vaccine development landscape","volume":"19","author":"Andreadakis","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S0140-6736(23)01514-3","article-title":"mRNA vaccines do not stop with COVID-19","volume":"402","author":"Zhou","year":"2023","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","article-title":"Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer","volume":"618","author":"Rojas","year":"2023","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.jconrel.2022.12.039","article-title":"Anti-PEG antibodies before and after a first dose of comirnaty\u00ae (mRNA-LNP-Based SARS-CoV-2 Vaccine)","volume":"354","author":"Bavli","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1111\/all.15187","article-title":"The form of PEG matters: PEG conjugated with lipids and not PEG alone could be the specific form involved in allergic reactions to COVID-19 vaccines","volume":"77","author":"Cabanillas","year":"2022","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-021-01311-z","article-title":"mRNA Vaccine: A potential therapeutic strategy","volume":"20","author":"Wang","year":"2021","journal-title":"Mol. Cancer."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.ymthe.2019.03.002","article-title":"mRNA: A novel avenue to antibody therapy?","volume":"27","author":"Schlake","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16982","DOI":"10.1021\/acsnano.1c04996","article-title":"Lipid nanoparticles-from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement","volume":"15","author":"Tenchov","year":"2021","journal-title":"ACS Nano."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.ijpharm.2021.120586","article-title":"mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability","volume":"601","author":"Schoenmaker","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103505","DOI":"10.1016\/j.drudis.2023.103505","article-title":"Design of lipid-based nanoparticles for delivery of therapeutic nucleic acids","volume":"28","author":"Kont","year":"2023","journal-title":"Drug Discov. Today"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.jconrel.2022.09.031","article-title":"Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of pegylated products","volume":"351","author":"Ibrahim","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.xphs.2023.11.001","article-title":"Treatment-induced and pre-existing anti-PEG antibodies: Prevalence, clinical implications, and future perspectives","volume":"113","author":"Gaballa","year":"2024","journal-title":"J. Pharm. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.chembiol.2019.02.001","article-title":"Anti-PEG antibodies inhibit the anticoagulant activity of PEGylated aptamers","volume":"26","author":"Moreno","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lenders, M., Feidicker, L.M., Brand, S., and Brand, E. (2023). Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1266082"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.jconrel.2021.11.042","article-title":"Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement","volume":"341","author":"Dijkxhoorn","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1080\/14686996.2019.1627174","article-title":"PEGylated liposomes: Immunological responses","volume":"20","author":"Mohamed","year":"2019","journal-title":"Sci. Technol. Adv. Mater."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sa, S., Lee, C.W., Shim, S.R., Yoo, H., Choi, J., Kim, J.H., Lee, K., Hong, M., and Han, H.W. (2022). The safety of mRNA-1273, BNT162b2 and JNJ-78436735 COVID-19 vaccines: Safety monitoring for adverse events using real-world data. Vaccines, 10.","DOI":"10.3390\/vaccines10020320"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1039\/D2SC07047B","article-title":"Hidden hydrophobicity impacts polymer immunogenicity","volume":"14","author":"Yuan","year":"2023","journal-title":"Chem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ijpharm.2006.10.020","article-title":"ABA and BAB type triblock copolymers of PEG and PLA: A comparative study of drug release properties and \u201cstealth\u201d particle characteristics","volume":"334","author":"He","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1039\/D3CC06098E","article-title":"Engineering poly (ethylene glycol) particles for targeted drug delivery","volume":"60","author":"Li","year":"2024","journal-title":"Chem. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2301650","DOI":"10.1002\/adhm.202301650","article-title":"Anti-HER2 super stealth immunoliposomes for targeted-chemotherapy","volume":"12","author":"Canato","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10817","DOI":"10.1021\/acs.langmuir.8b02117","article-title":"Nanoengineering of poly (ethylene glycol) particles for stealth and targeting","volume":"34","author":"Cui","year":"2018","journal-title":"Langmuir"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/wnan.1339","article-title":"Anti-PEG Immunity: Emergence, characteristics, and unaddressed questions","volume":"7","author":"Yang","year":"2015","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jconrel.2023.09.003","article-title":"Accelerated blood clearance of PEGylated nanoparticles induced by PEG-based pharmaceutical excipients","volume":"363","author":"Miao","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chang, T., Chen, B., Wu, J., Cheng, T., and Roffler, S. (2022). Impact of anti-PEG antibody affinity on accelerated blood clearance of PEGylated epoetin beta in mice. Biomed. Pharmacother., 146.","DOI":"10.1016\/j.biopha.2021.112502"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s43094-022-00409-5","article-title":"Immunogenicity and clinical features relating to BNT162b2 messenger RNA COVID-19 vaccine, Ad26.COV2.S and ChAdOx1 adenoviral vector COVID-19 vaccines: A systematic review of non-interventional studies","volume":"8","author":"Iheanacho","year":"2022","journal-title":"Futur. J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e2140364","DOI":"10.1001\/jamanetworkopen.2021.40364","article-title":"Analysis of COVID-19 vaccine type and adverse effects following vaccination","volume":"4","author":"Beatty","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejpb.2018.02.019","article-title":"A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes","volume":"127","author":"Shimizu","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kong, Y.W., and Dreaden, E.C. (2022). PEG: Will it come back to you? Polyethelyne glycol immunogenicity, COVID vaccines, and the case for new PEG derivatives and alternatives. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.879988"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ymthe.2005.09.014","article-title":"Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes","volume":"13","author":"Judge","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jconrel.2024.01.003","article-title":"Development of anti-PEG IgG \/ IgM \/ IgE ELISA assays for profiling anti-PEG immunoglobulin response in PEG-sensitized individuals and patients with alpha-gal allergy","volume":"366","author":"Li","year":"2024","journal-title":"J. Control. Release"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.imbio.2015.06.005","article-title":"Anti-PEG IgM and complement system are required for the association of second doses of PEGylated liposomes with splenic marginal zone B cells","volume":"220","author":"Shimizu","year":"2015","journal-title":"Immunobiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7682","DOI":"10.1021\/acsnano.0c03648","article-title":"Complement activation: A potential threat on the safety of poly (ethylene glycol)-coated nanomedicines","volume":"14","author":"Gabizon","year":"2020","journal-title":"ACS Nano"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14022","DOI":"10.1021\/acsnano.1c05922","article-title":"Polyethylene glycol immunogenicity: Theoretical, clinical, and practical aspects of anti-polyethylene glycol antibodies","volume":"15","author":"Chen","year":"2021","journal-title":"ACS Nano"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/j.jaip.2018.12.003","article-title":"Immediate hypersensitivity to polyethylene glycols and polysorbates: More common than we have recognized","volume":"7","author":"Stone","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.jaip.2020.11.011","article-title":"Anti-PEG IgE in anaphylaxis associated with polyethylene glycol","volume":"9","author":"Zhou","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jconrel.2023.01.021","article-title":"Accelerated clearance by antibodies against methoxy PEG depends on PEGylation architecture","volume":"354","author":"Lin","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1023\/A:1012248721523","article-title":"Biodistribution of long-circulating PEG-grafted nanocapsules in mice: Effects of PEG chain length and density","volume":"18","author":"Carla","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1093\/eurheartj\/ehs232","article-title":"A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the reg1 system in patients with acute coronary syndromes: Results of the RADAR trial","volume":"34","author":"Povsic","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ajo.2006.10.007","article-title":"Vitreous injections of pegaptanib sodium triggering allergic reactions","volume":"143","author":"Steffensmeier","year":"2007","journal-title":"Am. J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/pds.3655","article-title":"Relative safety of peginesatide and epoetin alfa","volume":"23","author":"Weinhandl","year":"2014","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6288","DOI":"10.1002\/anie.200902672","article-title":"Poly (ethylene glycol) in drug delivery: Pros and cons as well as potential alternatives","volume":"49","author":"Knop","year":"2010","journal-title":"Angew. Chemie Int. Ed."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/cea.12760","article-title":"Immediate-type hypersensitivity to polyethylene glycols: A review","volume":"46","author":"Wenande","year":"2016","journal-title":"Clin. Exp. Allergy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.jaip.2020.09.029","article-title":"Polyethylene glycol-induced systemic allergic reactions (anaphylaxis)","volume":"9","author":"Sellaturay","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1208\/s12249-020-1640-4","article-title":"Effects of uncleavable and cleavable PEG-lipids with different molecular weights on accelerated blood clearance of PEGylated emulsions in beagle dogs","volume":"21","author":"Jiao","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4312","DOI":"10.1021\/acs.nanolett.0c01011","article-title":"Overcoming nanoparticle-mediated complement activation by surface PEG-pairing","volume":"20","author":"Pannuzzo","year":"2020","journal-title":"Nano Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"121365","DOI":"10.1016\/j.ijpharm.2021.121365","article-title":"Evasion of the accelerated blood clearance phenomenon by branched PEG lipid derivative coating of nanoemulsions","volume":"612","author":"Liu","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1021\/acs.molpharmaceut.0c00149","article-title":"In vitro and in vivo behavior of liposomes decorated with PEGs with different chemical features","volume":"17","author":"Mastrotto","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jconrel.2012.11.016","article-title":"Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon","volume":"165","author":"Shiraishi","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jconrel.2008.05.009","article-title":"Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives","volume":"130","author":"Xu","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.2147\/IJN.S24344","article-title":"Effects of a novel pH-sensitive liposome with cleavable esterase-catalyzed and pH-responsive double smart mPEG lipid derivative on ABC phenomenon","volume":"6","author":"Chen","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.jconrel.2014.04.047","article-title":"Designer lipids for drug delivery: From heads to tails","volume":"190","author":"Kohli","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.colsurfb.2006.02.006","article-title":"A reduction-triggered delivery by a liposomal carrier possessing membrane-permeable ligands and a detachable coating","volume":"49","author":"Maeda","year":"2006","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1021\/bc025632k","article-title":"Novel intracellular delivery system of antisense oligonucleotide by self-assembled hybrid micelles composed of DNA\/PEG conjugate and cationic fusogenic peptide","volume":"14","author":"Jeong","year":"2003","journal-title":"Bioconjug. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ymthe.2004.11.006","article-title":"Toward synthetic viruses: Endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo","volume":"11","author":"Walker","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0168-3659(03)00232-3","article-title":"Acid-triggered release via dePEGylation of DOPE Liposomes Containing acid-labile vinyl ether PEG-lipids","volume":"91","author":"Shin","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jddst.2019.01.004","article-title":"Effect of amide linkage of PEG-lipid conjugates on the stability and cytotoxic activity of goniodiol loaded in PEGylated liposomes","volume":"50","author":"Charoensit","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fam, S.Y., Chee, C.F., Yong, C.Y., Ho, K.L., Mariatulqabtiah, A.R., and Tan, W.S. (2020). Stealth coating of nanoparticles in drug-delivery systems. Nanomaterials, 10.","DOI":"10.3390\/nano10040787"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1021\/mp400703d","article-title":"Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for brush conformation","volume":"11","author":"Yang","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.addr.2015.09.012","article-title":"PEGylation as a strategy for improving nanoparticle-based drug and gene delivery","volume":"99","author":"Suk","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Xiao, Y., Lian, X., Sun, Y., Sung, Y.-C., Vaidya, A., Chen, Z., Gupta, A., Chatterjee, S., Zheng, L., and Guerrero, E. (2025). High-density brush-shaped polymer lipids reduce anti-PEG antibody binding for repeated administration of mRNA therapeutics. Nat. Mater.","DOI":"10.1038\/s41563-024-02116-3"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jconrel.2009.04.006","article-title":"Effect of siRNA in PEG-coated siRNA lipoplex on anti-PEG IgM production","volume":"137","author":"Tagami","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00280-011-1664-2","article-title":"Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients","volume":"69","author":"Zamboni","year":"2012","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jconrel.2006.08.017","article-title":"Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection","volume":"115","author":"Ishida","year":"2006","journal-title":"J. Control. Release"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11769","DOI":"10.1021\/acsnano.2c04543","article-title":"Anti-PEG antibodies boosted in humans by SARS-CoV-2 lipid nanoparticle mRNA Vaccine","volume":"16","author":"Ju","year":"2022","journal-title":"ACS Nano"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1124\/jpet.104.078113","article-title":"Immunogenicity and rapid blood clearance of liposomes containing polyethylene glycol-lipid conjugates and nucleic acid","volume":"312","author":"Semple","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s11095-012-0934-y","article-title":"Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: Effects of polymer dose, PEG coating, and encapsulated anticancer drug","volume":"30","author":"Saadati","year":"2013","journal-title":"Pharm. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.jaci.2015.10.034","article-title":"Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer","volume":"137","author":"Ganson","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"10661","DOI":"10.1021\/acs.analchem.6b03109","article-title":"Measurement of pre-existing IgG and IgM antibodies against polyethylene glycol in healthy individuals","volume":"88","author":"Chen","year":"2016","journal-title":"Anal. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1016\/j.jaci.2016.04.058","article-title":"Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer","volume":"138","author":"Povsic","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.ijpharm.2012.11.015","article-title":"Abrogation of the accelerated blood clearance phenomenon by SOXL regimen: Promise for clinical application","volume":"441","author":"Nagao","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jconrel.2013.07.026","article-title":"The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage","volume":"172","author":"Kiwada","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0168-3659(02)00462-5","article-title":"Accelerated clearance of PEGylated liposomes in rats after repeated injections","volume":"88","author":"Ishida","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jconrel.2005.04.003","article-title":"Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes","volume":"105","author":"Ishida","year":"2005","journal-title":"J. Control. Release"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Guerrini, G., Gioria, S., Sauer, A.V., Lucchesi, S., Montagnani, F., Pastore, G., Ciabattini, A., Medaglini, D., and Calzolai, L. (2022). Monitoring anti-PEG antibodies level upon repeated lipid nanoparticle-based COVID-19 Vaccine administration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23168838"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1056\/NEJMra2035343","article-title":"Maintaining safety with SARS-CoV-2 vaccines","volume":"384","author":"Castells","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/hae.14930","article-title":"Safety and efficacy of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A: Results of an interventional, post-marketing study","volume":"30","author":"Holme","year":"2024","journal-title":"Haemophilia"},{"key":"ref_81","first-page":"100575","article-title":"Successful desensitization of Pegvaliase (Palynziq\u00ae) in a patient with phenylketonuria","volume":"23","author":"Patrawala","year":"2020","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1177\/2048872617703065","article-title":"Direct factor IXa inhibition with the RNA-aptamer pegnivacogin reduces platelet reactivity in vitro and residual platelet aggregation in patients with acute coronary syndromes","volume":"8","author":"Staudacher","year":"2019","journal-title":"Eur. Heart J. Acute Cardiovasc. Care"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"8496246","DOI":"10.1155\/2017\/8496246","article-title":"Long-term safety of PEGylated coagulation factor VIII in the immune-deficient rowett nude rat","volume":"2017","author":"Rasmussen","year":"2017","journal-title":"J. Toxicol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1182\/bloodadvances.2022007529","article-title":"The safety and efficacy of N8-GP (turoctocog alfa pegol) in previously untreated pediatric patients with hemophilia A","volume":"7","author":"Male","year":"2023","journal-title":"Blood Adv."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1021\/acs.accounts.9b00228","article-title":"Survey of clinical translation of cancer nanomedicines-lessons learned from successes and failures","volume":"52","author":"He","year":"2019","journal-title":"Acc. Chem. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jconrel.2020.04.011","article-title":"Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon","volume":"323","author":"Takata","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.echo.2021.05.002","article-title":"Expert consensus statement from the American Society of Echocardiography on hypersensitivity reactions to ultrasound enhancing agents in patients with allergy to polyethylene glycol","volume":"34","author":"Lindner","year":"2021","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.echo.2021.09.014","article-title":"Ultrasound-enhancing agents and associated adverse reactions: A potential connection to the COVID-19 vaccines?","volume":"35","author":"Soni","year":"2022","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Bell, G. (2016). Quantifying western blots: None more black. BMC Biol., 14.","DOI":"10.1186\/s12915-016-0339-1"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"112669","DOI":"10.1016\/j.jim.2019.112669","article-title":"A generic method for the detection of polyethylene glycol specific IgG and IgM antibodies in human serum","volume":"474","author":"Ehlinger","year":"2019","journal-title":"J. Immunol. Methods"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.toxrep.2020.12.022","article-title":"Flow cytometry analysis of anti-polyethylene glycol antibodies in human plasma","volume":"8","author":"Fang","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1208\/s12248-015-9799-4","article-title":"Development of a generic anti-PEG antibody assay using BioScale\u2019s Acoustic Membrane MicroParticle technology","volume":"17","author":"Dong","year":"2015","journal-title":"AAPS J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1208\/s12248-018-0228-3","article-title":"Generic anti-PEG antibody assay on ProterixBio\u2019s (formerly BioScale) ViBE platform shows poor reproducibility","volume":"20","author":"Chilewski","year":"2018","journal-title":"AAPS J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.addr.2020.07.024","article-title":"Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals","volume":"154\u2013155","author":"Kozma","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/17576180.2024.2442198","article-title":"Development of a validated novel bead extraction method for the detection of anti-PEG antibodies in human serum","volume":"17","author":"Williams","year":"2025","journal-title":"Bioanalysis"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"9315","DOI":"10.1021\/acsnano.9b03942","article-title":"Pseudo-anaphylaxis to polyethylene glycol (PEG)-coated liposomes: Roles of anti-PEG IgM and complement activation in a porcine model of human infusion reactions","volume":"13","author":"Kozma","year":"2019","journal-title":"ACS Nano"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5672","DOI":"10.1021\/acs.molpharmaceut.4c00628","article-title":"Effect of Anti-PEG Antibody on Immune Response of MRNA-Loaded Lipid Nanoparticles","volume":"21","author":"Omata","year":"2024","journal-title":"Mol. Pharm."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Neun, B.W., Barenholz, Y., Szebeni, J., and Dobrovolskaia, M.A. (2018). Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro. Molecules, 23.","DOI":"10.3390\/molecules23071700"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/bjh.16254","article-title":"Acute Lymphoblastic Leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker","volume":"189","author":"Kloos","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/cncr.22739","article-title":"Antibody against poly (ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients","volume":"110","author":"Armstrong","year":"2007","journal-title":"Cancer"},{"key":"ref_101","unstructured":"Veronese, F.M. (2009). The occurrence, induction, specificity and potential effect of antibodies against poly(ethylene glycol). PEGylated Protein Drugs: Basic Science and Clinical Applications, Birkh\u00e4user. [1st ed.]."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"8217","DOI":"10.1021\/acs.analchem.7b02447","article-title":"Sensitive and quantitative detection of anti-poly (ethylene glycol) (PEG) antibodies by methoxy-PEG-coated surface plasmon resonance sensors","volume":"89","author":"Zhang","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1021\/bc200551b","article-title":"Role of the methoxy group in immune responses to mPEG-protein conjugates","volume":"23","author":"Sherman","year":"2012","journal-title":"Bioconjug. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.molimm.2013.07.014","article-title":"Selectivity of binding of PEGs and PEG-like oligomers to anti-PEG antibodies induced by methoxyPEG-proteins","volume":"57","author":"Saifer","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Swainson, S.M.E., Styliari, I.D., Taresco, V., and Garnett, M.C. (2019). Poly (glycerol adipate) (PGA), an enzymatically synthesized functionalizable polyester and versatile drug delivery carrier: A literature update. Polymers, 11.","DOI":"10.3390\/polym11101561"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e2001382","DOI":"10.1002\/adhm.202001382","article-title":"Poly(2-oxazoline)- and poly(2-oxazine)-based self-assemblies, polyplexes, and drug nanoformulations-an update","volume":"10","author":"Luxenhofer","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"5142","DOI":"10.1021\/acs.biomac.3c00683","article-title":"Poly(2-oxazoline)\/saRNA polyplexes for targeted and nonviral gene delivery","volume":"24","author":"Hayes","year":"2023","journal-title":"Biomacromolecules"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2411354","DOI":"10.1002\/smll.202411354","article-title":"Poly(2-ethyl-2-oxazoline) (POx) as poly (ethylene glycol) (PEG)-lipid substitute for lipid nanoparticle formulations","volume":"21","author":"Holick","year":"2025","journal-title":"Small"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1039\/D4BM01541J","article-title":"Zwitterionic polymer with minimal reactivity against PEG antibodies to enhance the therapeutic effects of cytokine-targeting DNA aptamer","volume":"13","author":"Cho","year":"2025","journal-title":"Biomater. Sci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6125","DOI":"10.1021\/acsami.4c20890","article-title":"Zwitterionic poly (ethylene glycol) nanoparticles minimize protein adsorption and immunogenicity for improved biological fate","volume":"17","author":"Tian","year":"2025","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_111","first-page":"86","article-title":"Engineering LNPs with polysarcosine lipids for mRNA delivery","volume":"37","author":"Kang","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1002\/pol.20200375","article-title":"Poly(2-[dimethylamino]ethyl methacrylate)-b-poly (hydroxypropyl methacrylate)\/DNA polyplexes in aqueous solutions","volume":"58","author":"Sentoukas","year":"2020","journal-title":"J. Polym. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.progpolymsci.2018.01.002","article-title":"Polysarcosine-containing copolymers: Synthesis, characterization, self-assembly, and applications","volume":"81","author":"Birke","year":"2018","journal-title":"Prog. Polym. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1021\/acs.bioconjchem.8b00237","article-title":"Polysarcosine as an alternative to PEG for therapeutic protein conjugation","volume":"29","author":"Hu","year":"2018","journal-title":"Bioconjug. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Wilhelmy, C., Keil, I.S., Uebbing, L., Schroer, M.A., Franke, D., Nawroth, T., Barz, M., Sahin, U., Haas, H., and Diken, M. (2023). Polysarcosine-functionalized mRNA lipid nanoparticles tailored for immunotherapy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15082068"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2023.02.021","article-title":"Polysarcosine-based lipid formulations for intracranial delivery of mRNA","volume":"356","author":"Bi","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"10634","DOI":"10.1021\/acsanm.0c01834","article-title":"Polysarcosine-functionalized lipid nanoparticles for therapeutic mRNA delivery","volume":"3","author":"Nogueira","year":"2020","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Caprifico, A.E., Foot, P.J.S., Polycarpou, E., and Calabrese, G. (2022). Advances in chitosan-based CRISPR\/Cas9 delivery systems. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091840"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"355","DOI":"10.7150\/thno.29137","article-title":"Chemotherapy priming of the pancreatic tumor microenvironment promotes delivery and anti-metastasis efficacy of intravenous low-molecular-weight heparin-coated lipid-siRNA complex","volume":"9","author":"Yu","year":"2019","journal-title":"Theranostics"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cis.2019.03.007","article-title":"Chitosan for gene delivery: Methods for improvement and applications","volume":"268","author":"Chuan","year":"2019","journal-title":"Adv. Colloid. Interface Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:54:42Z","timestamp":1760032482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":120,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["pharmaceutics17060798"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17060798","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]}}}