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For example, surface functionalization with small molecules or linear hydrophilic polymers is commonly used to tune the interaction of nanoparticles with proteins and cells. However, it is challenging to control the location of functional groups within the shell for conventional nanoparticles. Nanoparticle surfaces composed of shape\u2010persistent bottlebrush polymers allow hierarchical control over the nanoparticle shell but the effect of the bottlebrush backbone on biological interactions is still unknown. The synthesis is reported of novel heterobifunctional poly(ethylene glycol) (PEG)\u2010norbornene macromonomers modified with various small molecules to form bottlebrush polymers with different backbone chemistries. It is demonstrated that micellar nanoparticles composed of poly(lactic acid) (PLA)\u2010PEG bottlebrush block copolymer (BBCP) with neutral and cationic backbone modifications exhibit significantly reduced cellular uptake compared to conventional unmodified BBCPs. Furthermore, the nanoparticles display long blood circulation half\u2010lives of \u224822\u00a0hours and enhanced tumor accumulation in mice. Overall, this work sheds light on the importance of the bottlebrush polymer backbone and provides a strategy to improve the performance of nanoparticles in biomedical applications.<\/jats:p>","DOI":"10.1002\/adhm.202304040","type":"journal-article","created":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T23:29:45Z","timestamp":1715470185000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Modifying the Backbone Chemistry of PEG\u2010Based Bottlebrush Block Copolymers for the Formation of Long\u2010Circulating Nanoparticles"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4848-713X","authenticated-orcid":false,"given":"Julian","family":"Grundler","sequence":"first","affiliation":[{"name":"Department of Chemistry and Department of Biomedical Engineering Yale University  New Haven CT 06511 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang\u2010Hee","family":"Whang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Yale University  New Haven CT 06511 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangsoo","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Polymer Science &amp; Engineering and Environmental Engineering Inha University  Incheon 22212 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Anna","family":"Savan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Yale University  New Haven CT 06511 USA"},{"name":"Medical Scientist Training Program Yale School of Medicine  New Haven CT 06510 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjiang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Department of Chemistry Yale University  New Haven CT 06511 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2163-549X","authenticated-orcid":false,"given":"W. Mark","family":"Saltzman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Yale University  New Haven CT 06511 USA"},{"name":"Department of Cellular &amp; Molecular Physiology and Department of Dermatology Yale School of Medicine  New Haven CT 06510 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0669-6"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.120780"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq0603"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nantod.2016.04.008"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-018-0279-x"},{"key":"e_1_2_7_6_1","first-page":"11","volume":"136","author":"Liao L.","year":"2014","journal-title":"J. Am. Chem. 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