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An approach that addresses both drawbacks is protein encapsulation within in a polymeric nanoparticle, which is effective but introduces the additional challenge of destabilizing the nanoparticle shell in clinically relevant locations. This study examined the effects of crosslinking self\u2010assembled poly(<jats:sc>l<\/jats:sc>\u2010lysine)\u2010grafted\u2010poly(ethylene glycol) nanoparticles with redox\u2010responsive 3,3\u2032\u2010dithiobis(sulfosuccinimidyl propionate) (DTSSP) to achieve nanoparticle destabilization in a reductive environment. The polymer\u2010protein nanoparticles (DTSSP NPs) were formed through electrostatic self\u2010assembly and crosslinked with DTSSP, which contains a glutathione\u2010reducible disulfide. As glutathione is upregulated in various cancers, DTSSP NPs could display destabilization within cancer cells. A library of DTSSP NPs was formed with varying copolymer to protein (C:P) and crosslinker to protein (X:P) mass ratios and characterized by size and encapsulation efficiency. DTSSP NPs with a 7:1 C:P ratio and 2:1 X:P ratio were further characterized by stability in the presence proteases and reducing agents. DTSSP NPs fully encapsulated the model protein and displayed 81% protein release when incubated with 5\u2009mM dithiothreitol for 12\u2009hr. This study contributes to understanding stimulus\u2010responsive crosslinking of polymeric nanoparticles and could be foundational to clinical administration of therapeutic proteins.<\/jats:p>","DOI":"10.1002\/bit.27369","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T10:34:45Z","timestamp":1588588485000},"page":"2504-2515","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effect of redox\u2010responsive DTSSP crosslinking on poly(<scp>l<\/scp>\u2010lysine)\u2010grafted\u2010poly(ethylene glycol) nanoparticles for delivery of proteins"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1158-055X","authenticated-orcid":false,"given":"Joshua","family":"Seaberg","sequence":"first","affiliation":[{"name":"School of Chemical Engineering Oklahoma State University  Stillwater Oklahoma"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Flynn","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Oklahoma State University  Stillwater Oklahoma"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Oklahoma State University  Stillwater Oklahoma"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5872-5595","authenticated-orcid":false,"given":"Joshua D.","family":"Ramsey","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering Oklahoma State University  Stillwater Oklahoma"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,6,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/c1py00034a"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420006636.ch13"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.07.019"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2009.033"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.9.8.1503"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2007.05.037"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8QM00460A"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC05031G"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2016.01.050"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-346"},{"key":"e_1_2_7_12_1","volume-title":"Proteins: structures and molecular properties","author":"Creighton T. 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