Poly(2-oxazoline)s and poly(2-oxazine)s: An overview of stealth properties, pharmacokinetics, and immunogenicity

For over four decades, poly(ethylene glycol) (PEG) has been the undisputed gold standard for conferring stealth properties to nanomedicines and polymer therapeutics. However, the widespread presence of pre-existing anti-PEG antibodies in the general population, which was intensified by recent mRNA COVID-19 vaccination campaigns, has exposed critical immunological liabilities, including accelerated blood clearance, hypersensitivity reactions and reduced therapeutic efficacy. Poly(2-oxazoline)s, particularly poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-ethyl-2-oxazoline) (PEtOx), have emerged as promising PEG alternatives. Their hydrolytically stable amide backbone, absence of ether oxygens (key recognition motifs for anti-PEG antibodies), tunable hydrophilicity, chemical versatility, tailor-made properties and excellent antifouling characteristics position them as ideal stealth candidates. This review discusses the progress that has been made on poly(2-oxazoline)s as alternative to PEG by discussing the state-of-the-art in poly(2-oxazoline) stealth/antifouling properties, pharmacokinetics, and immunogenicity, structured by polymer type, namely PMeOx, PEtOx, and other polymers, such as chiral poly(2-oxazoline)s and poly(2-oxazine)s. This review aims to give an overview of the current status, which can be used as starting point for getting acquainted with poly(2-oxazoline)s as PEG-alternatives for those new to the field and as source of inspiration for future research in the area.