{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:54:57Z","timestamp":1791572097960,"version":"4.3.4"},"reference-count":91,"publisher":"Wiley","issue":"28","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG\u201018\u2010133\u201001\u2010CDD"],"award-info":[{"award-number":["RSG\u201018\u2010133\u201001\u2010CDD"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F32CA247352"],"award-info":[{"award-number":["F32CA247352"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long\u2010lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, this study explored the ability of a slow\u2010releasing injectable hydrogel depot to reduce dose\u2010limiting toxicities of immunostimulatory CD40\u00a0agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer\u2010nanoparticle (PNP) hydrogel system is leveraged that exhibits shear\u2010thinning and yield\u2010stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel\u2010based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a\u2010loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10\u00a0melanoma model. PNP hydrogels, therefore, represent a facile, drug\u2010agnostic method to ameliorate immune\u2010related adverse effects and explore locoregional delivery of immunostimulatory drugs.<\/jats:p>","DOI":"10.1002\/advs.202103677","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T03:11:07Z","timestamp":1660705867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Injectable Nanoparticle\u2010Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8230-4945","authenticated-orcid":false,"given":"Santiago","family":"Correa","sequence":"first","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily L.","family":"Meany","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6536-3027","authenticated-orcid":false,"given":"Emily C.","family":"Gale","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Stanford University School of Medicine  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Klich","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5117-7127","authenticated-orcid":false,"given":"Olivia M.","family":"Saouaf","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron T.","family":"Mayer","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zunyu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine S.","family":"Liong","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryanne A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin L.","family":"Maikawa","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail K.","family":"Grosskopf","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Mann","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Idoyaga","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Stanford ChEM\u2010H Institute Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Stanford Cancer Institute Stanford University School of Medicine  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-7126","authenticated-orcid":false,"given":"Eric A.","family":"Appel","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford CA 94305 USA"},{"name":"Stanford ChEM\u2010H Institute Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Stanford Cancer Institute Stanford University School of Medicine  Stanford CA 94305 USA"},{"name":"Department of Pediatrics \u2013 Endocrinology Stanford University School of Medicine  Stanford CA 94305 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003634"},{"key":"e_1_2_9_1_2","first-page":"185","volume":"41","author":"Alexander W.","year":"2016","journal-title":"P T"},{"key":"e_1_2_9_1_3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"e_1_2_9_1_4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504030"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8172"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad7118"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2015.05.013"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-017-0329-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0014-x"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00168"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1586"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2015.05.011"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.008"},{"key":"e_1_2_9_6_3","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.25"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0215"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4200"},{"key":"e_1_2_9_7_3","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0835"},{"key":"e_1_2_9_7_4","doi-asserted-by":"publisher","DOI":"10.1177\/2515135518763280"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00315"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-1340"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-014-1650-8"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2013.245"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0258"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0061"},{"key":"e_1_2_9_10_3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.08.3311"},{"key":"e_1_2_9_10_4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198443"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30532-5"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1320"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0182"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600146"},{"key":"e_1_2_9_12_3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810566115"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.0c00732"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130066"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21024-7"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.202000295"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/2022.04.20.488959"},{"key":"e_1_2_9_18_1","author":"Hernandez H. L.","year":"2020","journal-title":"Macromol. Biosci."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao1710"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.08.067"},{"key":"e_1_2_9_19_3","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-0916-2"},{"key":"e_1_2_9_19_4","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002852"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-062518-045435"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.107.040071"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.9b06504"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10147"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/adtp.202000242"},{"key":"e_1_2_9_22_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0442-z"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.3.1588"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000624"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-014-8491-6"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep26996"},{"key":"e_1_2_9_24_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2006.12.002"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000017"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00782.x"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0405191"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7610"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2888"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.01.056"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.03.067"},{"key":"e_1_2_9_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3343"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-0091"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.11.021"},{"key":"e_1_2_9_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.8b02019"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-02932-5"},{"key":"e_1_2_9_34_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02030"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-552729"},{"key":"e_1_2_9_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0343-9"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay3575"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601145"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0067"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1524"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1653744"},{"key":"e_1_2_9_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32141"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c01177"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan0401"},{"key":"e_1_2_9_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw2614"},{"key":"e_1_2_9_42_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.01.007"},{"key":"e_1_2_9_42_4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16838-w"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3791\/62234"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2019-CT089"},{"key":"e_1_2_9_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13061302"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.08.014"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.10.10.13976"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3265"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-84858-7"},{"key":"e_1_2_9_49_1","volume-title":"Maximum Entropy Econometrics: Robust Estimation with Limited Data","author":"Golan A.","year":"1997"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/93.3.491"},{"key":"e_1_2_9_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-S1-S2"},{"key":"e_1_2_9_51_1","volume-title":"Biometry: The Principles and Practice of Statistics in Biological Research","author":"Sokal R.","year":"1981"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/508092"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1198\/jasa.2010.tm09415"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202103677","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202103677","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202103677","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202103677","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T18:08:17Z","timestamp":1759774097000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202103677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,17]]},"references-count":91,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1002\/advs.202103677"],"URL":"https:\/\/doi.org\/10.1002\/advs.202103677","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.27.449987","asserted-by":"object"}]},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,17]]},"assertion":[{"value":"2021-08-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2103677"}}