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This ultimate goal is restricted by the low immunogenicity of conserved influenza epitopes. Layered protein nanoparticles composed of well\u2010designed conserved influenza structures have shown improved immunogenicity with new physical and biochemical features. Herein, structure\u2010stabilized influenza matrix protein 2 ectodomain (M2e) and M2e\u2010neuraminidase fusion (M2e\u2010NA) recombinant proteins are generated and M2e protein nanoparticles and double\u2010layered M2e\u2010NA protein nanoparticles are produced by ethanol desolvation and chemical crosslinking. Immunizations with these protein nanoparticles induce immune protection against different viruses of homologous and heterosubtypic NA in mice. Double\u2010layered M2e\u2010NA protein nanoparticles induce higher levels of humoral and cellular responses compared with their comprising protein mixture or M2e nanoparticles. Strong cytotoxic T cell responses are induced in the layered M2e\u2010NA protein nanoparticle groups. Antibody responses contribute to the heterosubtypic NA immune protection. The protective immunity is long lasting. These results demonstrate that double\u2010layered protein nanoparticles containing structure\u2010stabilized M2e and NA can be developed into a universal influenza vaccine or a synergistic component of such vaccines. Layered protein nanoparticles can be a general vaccine platform for different pathogens.<\/jats:p>","DOI":"10.1002\/adhm.201901176","type":"journal-article","created":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T02:55:50Z","timestamp":1576464950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Double\u2010Layered M2e\u2010NA Protein Nanoparticle Immunization Induces Broad Cross\u2010Protection against Different Influenza Viruses in Mice"],"prefix":"10.1002","volume":"9","author":[{"given":"Ye","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Deng","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert X.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latika","family":"Luthra","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Dong","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zou","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Moo","family":"Kang","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1561-4318","authenticated-orcid":false,"given":"Bao\u2010Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Inflammation Immunity &amp; Infection Georgia State University Institute for Biomedical Sciences  100 Piedmont Ave NE Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,15]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3927"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.246"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1805713115"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.4049\/jimmunol.139.6.2010","volume":"139","author":"Johansson B. 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