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While the recombinant protein\u2010based vaccine proves highly effective, it encounters supply chain challenges due to a shortage of the necessary adjuvant. Messenger RNA (mRNA)\u2010based vaccines can be rapidly produced on a large scale, but their effectiveness relies on efficient delivery and sequence design. Here, an mRNA\u2010based VZV vaccine using a synergistic lipid nanoparticle (Syn\u2010LNP) containing two different ionizable lipids is developed. Syn\u2010LNP shows superior mRNA expression compared to LNPs formulated with either type of ionizable lipid and to a commercialized LNP. After encapsulating VZV glycoprotein E (gE)\u2010encoding mRNA, mgE@Syn\u2010LNP induces robust humoral and cellular immune responses in two strains of mice. The magnitude of these responses is similar to that induced by adjuvanted recombinant gE proteins and significantly higher than that observed with live\u2010attenuated VZV. mgE@Syn\u2010LNP exhibits durable humoral responses for over 7 months without obvious adverse effects. In addition, mgE@Syn\u2010LNP protects vaccinated guinea pigs against live VZV challenges. Preliminary studies on the mRNA antigen design reveal that the removal of glycosylation sites of gE greatly reduces its immune responses. Collectively, Syn\u2010LNP encapsulating gE\u2010encoded mRNA holds great promise as a shingles vaccine.<\/jats:p>","DOI":"10.1002\/adma.202310886","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T15:49:02Z","timestamp":1703519342000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A Synergistic Lipid Nanoparticle Encapsulating mRNA Shingles Vaccine Induces Potent Immune Responses and Protects Guinea Pigs from Viral Challenges"],"prefix":"10.1002","volume":"36","author":[{"given":"Xingdi","family":"Cheng","sequence":"first","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences CAS Key Laboratory of Colloid Interface and Chemical Thermodynamics Institute of Chemistry Chinese Academy of Sciences  Beijing 100190 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 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