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By forming a steric barrier at the nanoparticle surface, PEG\u2010lipids reduce protein adsorption and extend circulation times. Additionally, PEG\u2010lipids are increasingly functionalized with targeting moieties, representing a primary strategy to enable selective delivery. However, accumulating evidence indicates that PEG\u2010lipids are not static components but instead undergo dynamic dissociation, or \u201cshedding,\u201d upon exposure to biological environments. This interfacial exchange process alters nanoparticle behavior, promoting protein adsorption and accelerating clearance, while also enabling cellular interactions that facilitate uptake. Here, we present a conceptual framework for understanding PEG\u2010lipid shedding as a coupled thermodynamic and kinetic process influenced by lipid chemical structure, nanocarrier membrane properties, and interactions with biomolecules. By synthesizing recent findings across experimental systems, we identify key factors that link PEG\u2010lipid composition and nanoparticle architecture to desorption kinetics and biological outcomes. These insights provide guidance for the design of PEGylated nanomaterials with improved control over interfacial stability, immune recognition, and functional performance.<\/jats:p>","DOI":"10.1002\/smll.75613","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:42:26Z","timestamp":1789108946000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemical and Biological Determinants of PEG\u2010Lipid Shedding From Therapeutic Nanoparticles"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3583-4844","authenticated-orcid":false,"given":"Ethan P.","family":"Cisneros","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aadya S.","family":"Wijesekera","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6197-0703","authenticated-orcid":false,"given":"Lisa R.","family":"Volpatti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Northwestern University  Evanston Illinois USA"},{"name":"Department of Chemical and Biological Engineering Northwestern University  Evanston Illinois USA"},{"name":"Biohub  Chicago Illinois USA"},{"name":"International Institute for Nanotechnology Northwestern University  Evanston Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnanoscienceau.2c00062"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c04996"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201011533\u20101"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201023013\u20102"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00544"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010023\u201002044\u20105"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1NA00712B"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.114872"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.3c00174"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.5b08805"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202404784"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp500400k"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1553"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1127704"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578\u2010022\u201000529\u20107"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000811\u20109"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1515\/mr\u20102022\u20100047"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010024\u201002954\u2010y"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pdpdt.2022.102915"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2022.114614"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202106291"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010020\u20100669\u20106"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109256118"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010021\u201001127\u20102"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm0594"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2019.10.001"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.121339"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202304378"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010025\u201001330\u2010w"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2BM01846B"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2013.66"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","unstructured":"A.Gallud M. 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