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While the leading shingles vaccine, Shingrix, provides protection against herpes zoster virus for adults aged 50 and older, it is often associated with severe local and systemic reactogenicity, which limits vaccine compliance. Here, we report an injectable polymer\u2010nanoparticle (PNP) hydrogel platform for the sustained delivery of a shingles subunit vaccine to enhance immune responses while mitigating reactogenicity in aged mice. Hydrogel\u2010based vaccination elicited significantly more potent and durable humoral immune responses than Shingrix, while inflammatory cytokine levels remained below the limit of detection. Moreover, aged mice vaccinated with the hydrogel\u2010based vaccine exhibited robust antigen\u2010specific cellular immune responses. These findings demonstrate that controlling the temporal presentation of vaccine components can overcome age\u2010associated declines in immune responsiveness without inducing excessive inflammatory signaling. By decoupling immunogenicity from reactogenicity, our hydrogel\u2010based delivery strategy offers a promising approach to improve both the efficacy and tolerability of subunit vaccines for the elderly and may be broadly applicable to other vaccines targeting aging populations.<\/jats:p>","DOI":"10.1002\/advs.76481","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:10:03Z","timestamp":1783944603000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sustained Delivery of a Shingles Subunit Vaccine Overcomes Age\u2010Related Declines in Humoral and Cellular Immunity Relative to Shingrix"],"prefix":"10.1002","volume":"13","author":[{"given":"Ye Eun","family":"Song","sequence":"first","affiliation":[{"name":"Department of Materials Science &amp; Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben S.","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia M.","family":"Saouaf","sequence":"additional","affiliation":[{"name":"Department of Materials Science &amp; Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-0153","authenticated-orcid":false,"given":"Noah","family":"Eckman","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-7126","authenticated-orcid":false,"given":"E. 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