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However, their development is often impeded by unfavorable pharmacokinetic profiles and largely relies on the use of drug delivery systems to prolong their in vivo half\u2010life and suppress undesirable immunogenicity. Although a commercially established PEGylation technology based on protein conjugation with poly(ethylene glycol) (PEG)\u2014protective steric shield resolves some of the challenges, the search for alternatives continues. Noncovalent PEGylation, which mainly relies on multivalent (cooperative) interactions and high affinity (host\u2013guest) complexes formed between protein and PEG offers a number of potential advantages. Among them are dynamic or reversible protection of the protein with minimal loss of biological activity, drastically lower manufacturing costs, \u201cmix\u2010and\u2010match\u201d formulations approaches, and expanded scope of PEGylation targets. While a great number of innovative chemical approaches have been proposed in recent years, the ability to effectively control the stability of noncovalently assembled protein\u2013PEG complexes under physiological conditions presents a serious challenge for the commercial development of the technology. In an attempt to identify critical factors affecting pharmacological behavior of noncovalently linked complexes, this Review follows a hierarchical analysis of various experimental techniques and resulting supramolecular architectures. The importance of in vivo administration routes, degradation patterns of PEGylating agents, and a multitude of potential exchange reactions with constituents of physiological compartments are highlighted.<\/jats:p><jats:p>This article is categorized under:<jats:list list-type=\"simple\">\n<jats:list-item><jats:p>Therapeutic Approaches and Drug Discovery &gt; Emerging Technologies<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Nanotechnology Approaches to Biology &gt; Nanoscale Systems in Biology<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Therapeutic Approaches and Drug Discovery &gt; Nanomedicine for Oncologic Disease<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wnan.1897","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T05:25:01Z","timestamp":1683177901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Noncovalent PEGylation of 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