Tsai, Hsiao HanHsiao HanTsaiHuang, Ping HanPing HanHuangLin, Leon C.W.Leon C.W.LinYao, Bing YuBing YuYaoLiao, Wan TingWan TingLiaoPai, Chen HsuehChen HsuehPaiLiu, Yu HanYu HanLiuHUI-WEN CHENHu, Che Ming J.Che Ming J.Hu2023-06-082023-06-082023-01-012198-3844https://www.scopus.com/inward/record.uri?eid=2-s2.0-85153307370&doi=10.1002%2fadvs.202206521&partnerID=40&md5=e30961143dbffef4154d1faa8d5f43b4https://scholars.lib.ntu.edu.tw/handle/123456789/631971The highly conserved matrix protein 2 ectodomain (M2e) of influenza viruses presents a compelling vaccine antigen candidate for stemming the pandemic threat of the mutation-prone pathogen, yet the low immunogenicity of the diminutive M2e peptide renders vaccine development challenging. A highly potent M2e nanoshell vaccine that confers broad and durable influenza protectivity under a single vaccination is shown. Prepared via asymmetric ionic stabilization for nanoscopic curvature formation, polymeric nanoshells co-encapsulating high densities of M2e peptides and stimulator of interferon genes (STING) agonists are prepared. Robust and long-lasting protectivity against heterotypic influenza viruses is achieved with a single administration of the M2e nanoshells in mice. Mechanistically, molecular adjuvancy by the STING agonist and nanoshell-mediated prolongation of M2e antigen exposure in the lymph node follicles synergistically contribute to the heightened anti-M2e humoral responses. STING agonist-triggered T cell helper functions and extended residence of M2e peptides in the follicular dendritic cell network provide a favorable microenvironment that induces Th1-biased antibody production against the diminutive antigen. These findings highlight a versatile nanoparticulate design that leverages innate immune pathways for enhancing the immunogenicity of weak immunogens. The single-shot nanovaccine further provides a translationally viable platform for pandemic preparedness.enfollicular dendritic cells; germinal center; lymph node follicle targeting; matrix protein 2 ectodomain antigen; nanoshell; stimulator of interferon genes agonist; universal influenza vaccine[SDGs]SDG3journal article10.1002/advs.202206521370925802-s2.0-85153307370WOS:000974478900001https://api.elsevier.com/content/abstract/scopus_id/85153307370