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However, the development of nasal mRNA vaccines has been hampered by the lack of effective means to overcome the mucus barrier. Herein, ionizable lipid\u2010incorporated liquid lipid nanoparticles (iLLNs) capable of delivering mRNA cargo across airway mucosa are designed. Adjusting the ratios of ionizable and cationic lipids allows fine\u2010tuning of the p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    of iLLNs to the range of nasal mucosal pH (5.5\u20136.5), thus facilitating mucus penetration via the formation of near\u2010neutral, PEGylated muco\u2010inert surfaces. When nasally administered to mice, the top candidate iLLN\u20102\/mRNA complexes enable about 60\u2010fold greater reporter gene expression in the nasal cavity, compared to the benchmark mRNA\u2010lipid nanoparticles (ALC\u2010LNP) having the same lipid composition as that of BNT162b2 vaccine. Moreover, a prime\u2010boost intranasal immunization of iLLN\u20102\/mRNA complexes elicits a greater magnitude of SARS\u2010CoV\u20102 spike\u2010specific mucosal IgA and IgG response than ALC\u2010LNP, without triggering any noticeable inflammatory reactions. Taken together, these results provide useful insights for the design of nasally deliverable mRNA formulations for prophylactic applications.\n                  <\/jats:p>","DOI":"10.1002\/advs.202407383","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T05:45:51Z","timestamp":1738215951000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Muco\u2010Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0284-9210","authenticated-orcid":false,"given":"Nipuni","family":"Maniyamgama","sequence":"first","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-879X","authenticated-orcid":false,"given":"Ki Hyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi Wei","family":"Chang","sequence":"additional","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR)  8A Biomedical Grove, Immunos #05\u201013 Singapore 138648 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialing","family":"Lee","sequence":"additional","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melgious J. Y.","family":"Ang","sequence":"additional","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Jie","family":"Tan","sequence":"additional","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR)  8A Biomedical Grove, Immunos #05\u201013 Singapore 138648 Republic of Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa F. 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