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Adding polyethylene glycol (PEG) chains to the surface of nanoparticles (PEGylation) has been widely used to both enhance accumulation at the tumor site and increase blood circulation time. Recent work has also shown that immune cells (e.g., macrophages, dendritic cells, neutrophils) play an important role in the ability of NPs to effectively target and spread within a tumor. PEG chain characteristics such as size and branching affect how nanoparticles interact with tissues; however, it is unclear how PEGylation type affects NP uptake and cellular distribution in the tumor microenvironment. In this study, we evaluated the influence of both linear and branched PEGylation on nanoparticle biodistribution and uptake in tumor cells as well as tumor\u2010infiltrating immune cells. As compared to conventional surface coatings with linear PEG, we show that modifying PEG structure to a branched conformation increases nanoparticle accumulation in the spleen of tumor\u2010bearing mice, primarily due to significantly enhanced uptake by leukocytes. As compared to uncoated particles, we also found that nanoparticles densely coated with linear or branched PEG accumulated to a greater extent in tumors showing \u22658\u2010fold increases in uptake by tumor\u2010associated macrophages and dendritic cells. These studies provide insight into PEG architecture as a design parameter in nanomedicine that can facilitate the design of more effective cancer therapies.<\/jats:p>","DOI":"10.1002\/btm2.70098","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T02:43:06Z","timestamp":1765420986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>PEGylation<\/scp>\n                    strategies for enhanced nanoparticle delivery to tumor\u2010associated immune cells"],"prefix":"10.1002","volume":"11","author":[{"given":"Devorah","family":"Cahn","sequence":"first","affiliation":[{"name":"Cancer Biomaterials Engineering Section, Cancer Innovation Laboratory, Center for Cancer Research National Cancer Institute  Frederick Maryland USA"},{"name":"Fischell Department of Bioengineering University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Pal","sequence":"additional","affiliation":[{"name":"Cancer Biomaterials Engineering Section, Cancer Innovation Laboratory, Center for Cancer Research National Cancer Institute  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Stern","sequence":"additional","affiliation":[{"name":"Fischell Department of Bioengineering University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimit L.","family":"Patel","sequence":"additional","affiliation":[{"name":"Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc. 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