{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T05:40:18Z","timestamp":1793252418500,"version":"4.5.0"},"reference-count":43,"publisher":"Wiley","issue":"45","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Lipid nanoparticles (LNPs) are central to next\u2010generation vaccines, yet candidate selection remains largely empirical, limiting early identification of formulations associated with rare adverse events such as myocarditis. A better understanding of LNP composition\u2013immunogenicity relationships is therefore critical for rational vaccine design. Here, we profiled a panel of clinically relevant LNP formulations across complementary in vitro and in vivo models to define mechanisms underlying innate immune activation and adaptive responses. We identified three distinct cytokine programs: (i) a monocyte chemoattractant protein\u20101 (MCP\u20101)\u2010dominated inflammatory response associated with cytotoxic stress; (ii) inflammasome\u2010dependent interleukin\u20101 beta (IL\u20101\u03b2) secretion requiring pro\u2010inflammatory priming; and (iii) type I and II interferon\u2010dependent responses in which LNPs synergize with interferon gamma (IFN\u03b3) to amplify interferon gamma\u2010induced protein 10 (IP\u201010) production. Using a design of experiments (DoE) framework\u00a0with formulation feature analysis, we found that polyethylene glycol\u2010conjugated (PEGylated) lipid content and ionizable lipid identity are key modulators of the IFN\u03b3\/IP\u201010 axis, previously implicated in vaccine\u2010associated myocarditis. In vivo validation showed that innate cytokine responses are strongly influenced by lipid composition, whereas adaptive humoral and cellular responses correlate with transgene expression rather than cytokine magnitude. Collectively, these findings define relationships among LNP composition, cytokine induction, and vaccine efficacy, and provide a framework for rational design and screening of LNP\u2010based vaccines that maximize immunogenicity while minimizing reactogenicity.<\/jats:p>","DOI":"10.1002\/smll.74283","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:20:42Z","timestamp":1784550042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Defining Composition\u2013Cytokine Relationships Enables the Design of Lipid Nanoparticles with Programmed Immunogenicity"],"prefix":"10.1002","volume":"22","author":[{"given":"Adam Alexander","family":"Walters","sequence":"first","affiliation":[{"name":"Advanced Drug Delivery Pharmaceutical Sciences BioPharmaceuticals R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belal I.","family":"Hanafy","sequence":"additional","affiliation":[{"name":"Advanced Drug Delivery Pharmaceutical Sciences BioPharmaceuticals R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan\u2010En","family":"Lu","sequence":"additional","affiliation":[{"name":"Advanced Drug Delivery Pharmaceutical Sciences BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Marelli","sequence":"additional","affiliation":[{"name":"Discovery Sciences BioPharmaceuticals R&amp;D AstraZeneca  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Zam","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science School of Cancer &amp; 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