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Subunit boosters are considered a viable strategy to enhance BCG efficacy, which often wanes in adolescence. While many studies on booster subunit vaccines have concentrated on recombinant proteins, here we developed a novel modular peptide\u2010based subunit vaccine platform that is flexible, cold\u2010chain independent and customizable to diverse circumstances and populations. Each individual peptide building block consists of a linear arrangement comprising a 15\u2010leucine self\u2010assembly inducer moiety, a\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb) target epitope and an human leukocyte antigen E (HLA\u2010E) binding moiety, with each moiety separated by a triple lysine spacer. The building blocks, in any combination, are able to form a multiepitope nanoparticle. Six Mtb epitopes were selected to produce the self\u2010assembling and self\u2010adjuvating peptide\u2010based TB nano\u2010vaccine candidate PNx6. In vivo vaccination\u2010challenge experiments demonstrated that subcutaneous boost of parenteral BCG immunization with PNx6 significantly enhanced its immunogenicity and improved its protective efficacy in a murine model of TB by more than 5\u2010fold. This study presents evidence that purely amphiphilic peptides self\u2010assemble into self\u2010adjuvating nanoparticles with appropriate size and morphology for TB vaccination with\u00a0great potential for a multitude of other diseases.\n                  <\/jats:p>","DOI":"10.1002\/smll.202406874","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T01:43:11Z","timestamp":1736127791000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Modular Self\u2010Assembling and Self\u2010Adjuvanting Multiepitope Peptide Nanoparticle Vaccine Platform to Improve the Efficacy and Immunogenicity of BCG"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0541-3125","authenticated-orcid":false,"given":"Guangzu","family":"Zhao","sequence":"first","affiliation":[{"name":"Australian Institute of Tropical Health and Medicine James Cook University  Cairns &amp; Townsville QLD 4878 &amp; 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Townsville QLD 4878 &amp; 4811 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3446-6517","authenticated-orcid":false,"given":"Munish","family":"Puri","sequence":"additional","affiliation":[{"name":"Australian Institute of Tropical Health and Medicine James Cook University  Cairns &amp; Townsville QLD 4878 &amp; 4811 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6159-3688","authenticated-orcid":false,"given":"Wenbin","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chemistry &amp; Molecular Biosciences The University of Queensland  St Lucia QLD 4072 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4572-397X","authenticated-orcid":false,"given":"Istvan","family":"Toth","sequence":"additional","affiliation":[{"name":"School of Chemistry &amp; Molecular Biosciences The University of Queensland  St Lucia QLD 4072 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-6602","authenticated-orcid":false,"given":"Norelle","family":"Daly","sequence":"additional","affiliation":[{"name":"Australian Institute of Tropical Health and Medicine James Cook University  Cairns &amp; 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