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There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1\/Nrf2 protein\u2013protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2\u2010mimetic protein\u2010like polymer (PLP) to inhibit the Keap1\u2010Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1\u2010inhibiting PLPs (Keap1i\u2010PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub\u2010nanomolar concentrations in primary cardiomyocytes. Single\u2010digit mg kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    , single\u2010dose, intravenous PLP administration significantly improves cardiac function in rats post\u2010MI through immunomodulatory, anti\u2010apoptotic, and angiogenic mechanisms. Thus Keap1i\u2010PLPs disrupt key intracellular protein\u2013protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress\u2010driven diseases and conditions.\n                  <\/jats:p>","DOI":"10.1002\/adma.202417885","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:03:16Z","timestamp":1745568196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Protein\u2010Like Polymers Targeting Keap1\/Nrf2 as Therapeutics for Myocardial Infarction"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1022-8175","authenticated-orcid":false,"given":"Joshua M.","family":"Mesfin","sequence":"first","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego  La Jolla CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-3352","authenticated-orcid":false,"given":"Kendal P.","family":"Carrow","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program Department of Biomedical Engineering Northwestern University Feinberg School of Medicine  Chicago IL 60611 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Chen","sequence":"additional","affiliation":[{"name":"Program in Materials Science and Engineering Sanford Consortium for Regenerative Medicine University of California San Diego  La Jolla CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0531-8582","authenticated-orcid":false,"given":"Madeline P.","family":"Hopps","sequence":"additional","affiliation":[{"name":"Department of Chemistry International Institute for Nanotechnology Simpson\u2010Querrey Institute Chemistry of Life Processes Institute Northwestern University  Evanston IL 60208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoJo J.","family":"Holm","sequence":"additional","affiliation":[{"name":"Department of Chemistry International Institute for Nanotechnology Simpson\u2010Querrey Institute Chemistry of Life Processes Institute Northwestern University  Evanston IL 60208 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quincy P.","family":"Lyons","sequence":"additional","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego  La Jolla CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego  La Jolla CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jervaughn D.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Shu Chien\u2010Gene Lay Department of Bioengineering Sanford Consortium for Regenerative Medicine University of California San Diego  La Jolla CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6082-0324","authenticated-orcid":false,"given":"Assa","family":"Magassa","sequence":"additional","affiliation":[{"name":"Department of Chemistry Department of Materials Science &amp; 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