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Thermophobic adjuvants are synthesized by combining a rationally designed trehalose glycolipid vaccine adjuvant with thermoresponsive poly\u2010<jats:italic>N<\/jats:italic>\u2010isoporpylacrylamide (NIPAM) via reversible addition fragmentation chain transfer (RAFT) polymerization. The resulting thermophobic adjuvants exhibit LCSTs near 37 \u00b0C, and self\u2010assembled into nanoparticles with temperature\u2010dependent sizes (90\u2013270\u00a0nm). Thermophobic adjuvants activate HEK\u2010mMINCLE and other innate immune cell lines as well as primary mouse bone marrow derived dendritic cells (BMDCs) and bone marrow derived macrophages (BMDMs). Inflammatory cytokine production is\u00a0attenuated under conditions mimicking pyrexia (above the LCST) relative to homeostasis (37 \u00b0C) or below the LCST. This thermophobic behavior correlated with decreased adjuvant <jats:italic>R<\/jats:italic><jats:sub>g<\/jats:sub> is observed by DLS, as well as glycolipid\u2010NIPAM shielding interactions are observed by NOESY\u2010NMR. In vivo, thermophobic adjuvants enhance efficacy of a whole inactivated influenza A\/California\/04\/2009 virus vaccine, by increasing neutralizing antibody titers and CD4<jats:sup>+<\/jats:sup>\/44<jats:sup>+<\/jats:sup>\/62L<jats:sup>+<\/jats:sup> lung and lymph node central memory T cells, as well as providing better protection from morbidity after viral challenge relative to unadjuvanted control vaccine. Together, these results demonstrate the first adjuvants with potency regulated by temperature. This work envisions that with further investigation, this approach can enhance vaccine efficacy while maintaining safety.<\/jats:p>","DOI":"10.1002\/adhm.202202918","type":"journal-article","created":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T04:59:49Z","timestamp":1680325189000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Thermophobic Trehalose Glycopolymers as Smart C\u2010Type Lectin Receptor Vaccine Adjuvants"],"prefix":"10.1002","volume":"12","author":[{"given":"Aaron T.","family":"Hendricksen","sequence":"first","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahrzad","family":"Ezzatpour","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anunay J.","family":"Pulukuri","sequence":"additional","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin T.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatum J.","family":"Flanagan","sequence":"additional","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Frantz","sequence":"additional","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David W.","family":"Buchholz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac A.","family":"Monreal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie M.","family":"Sahler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7393-4846","authenticated-orcid":false,"given":"Amy E.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Astante Therapeutics Inc.  120 N Pine Street, Suite 270A Spokane WA 99202 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6879-8360","authenticated-orcid":false,"given":"Hector C.","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Cornell University  618 Tower Road Ithaca NY 14850 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3557-8123","authenticated-orcid":false,"given":"Rock J.","family":"Mancini","sequence":"additional","affiliation":[{"name":"Department of Chemistry Washington State University  1470 NE College Ave Pullman WA 99164 USA"},{"name":"Department of Chemistry and Biochemistry Miami University  651 E. 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