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However, purification is challenging as viral capsomeres show poor binding to chromatography media. In this study, the behavior of capsomeres in unfractionated bacterial lysate was compared with that for purified capsomeres, with or without added microbial DNA, to better understand reasons for poor bioprocess behavior. We show that aggregates or complexes form through the interaction between viral capsomeres and DNA, especially in bacterial lysates rich in contaminating DNA. The formation of these complexes prevents the target protein capsomeres from accessing the pores of chromatography media. We find that protein\u2013DNA interactions can be modulated by controlling the ionic strength of the buffer and that at elevated ionic strengths the protein\u2013DNA complexes dissociate. Capsomeres thus released show enhanced bind\u2010elute behavior on salt\u2010tolerant chromatography media. DNA could therefore be efficiently removed. We believe this is the first report of the use of an optimized salt concentration that dissociates capsomere\u2013DNA complexes yet enables binding to salt\u2010tolerant media. Post purification, assembly experiments indicate that DNA\u2013protein interactions can play a negative role during in vitro assembly, as DNA\u2013protein complexes could not be assembled into virus\u2010like particles, but formed worm\u2010like structures. This study reveals that the control over DNA\u2013protein interaction is a critical consideration during downstream process development for viral vaccines.<\/jats:p>","DOI":"10.1002\/bit.27687","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T06:21:35Z","timestamp":1611382895000},"page":"1688-1701","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Virus\u2010like particle preparation is improved by control over capsomere\u2010DNA interactions during chromatographic purification"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2421-5503","authenticated-orcid":false,"given":"Lukas","family":"Gerstweiler","sequence":"first","affiliation":[{"name":"School of Chemical Engineering and Advanced Materials The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7056-8572","authenticated-orcid":false,"given":"Jingxiu","family":"Bi","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Advanced Materials The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5922-5704","authenticated-orcid":false,"given":"Anton Peter Jacob","family":"Middelberg","sequence":"additional","affiliation":[{"name":"Division of Research and Innovation The University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2775"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.4155\/tde.14.74"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.06.087"},{"key":"e_1_2_9_5_1","unstructured":"Avallin J. 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