Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery
Abstract Intranasal delivery of mRNA vaccines offers promising opportunities to combat airborne viruses like SARS‐CoV‐2 by provoking mucosal immunity, which not only defends against respiratory infection but also prevents contagious transmission. However, the development of nasal mRNA vaccines has b...
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407383 |
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| author | Nipuni Maniyamgama Ki Hyun Bae Zi Wei Chang Jialing Lee Melgious J. Y. Ang Yong Jie Tan Lisa F. P. Ng Laurent Renia Kevin P. White Yi Yan Yang |
| author_facet | Nipuni Maniyamgama Ki Hyun Bae Zi Wei Chang Jialing Lee Melgious J. Y. Ang Yong Jie Tan Lisa F. P. Ng Laurent Renia Kevin P. White Yi Yan Yang |
| author_sort | Nipuni Maniyamgama |
| collection | DOAJ |
| description | Abstract Intranasal delivery of mRNA vaccines offers promising opportunities to combat airborne viruses like SARS‐CoV‐2 by provoking mucosal immunity, which not only defends against respiratory infection but also prevents contagious transmission. However, the development of nasal mRNA vaccines has been hampered by the lack of effective means to overcome the mucus barrier. Herein, ionizable lipid‐incorporated liquid lipid nanoparticles (iLLNs) capable of delivering mRNA cargo across airway mucosa are designed. Adjusting the ratios of ionizable and cationic lipids allows fine‐tuning of the pKa of iLLNs to the range of nasal mucosal pH (5.5–6.5), thus facilitating mucus penetration via the formation of near‐neutral, PEGylated muco‐inert surfaces. When nasally administered to mice, the top candidate iLLN‐2/mRNA complexes enable about 60‐fold greater reporter gene expression in the nasal cavity, compared to the benchmark mRNA‐lipid nanoparticles (ALC‐LNP) having the same lipid composition as that of BNT162b2 vaccine. Moreover, a prime‐boost intranasal immunization of iLLN‐2/mRNA complexes elicits a greater magnitude of SARS‐CoV‐2 spike‐specific mucosal IgA and IgG response than ALC‐LNP, without triggering any noticeable inflammatory reactions. Taken together, these results provide useful insights for the design of nasally deliverable mRNA formulations for prophylactic applications. |
| format | Article |
| id | doaj-art-e00b030ed4844ce7accceab01aa92e06 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-e00b030ed4844ce7accceab01aa92e062025-08-20T02:24:47ZengWileyAdvanced Science2198-38442025-03-011211n/an/a10.1002/advs.202407383Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA DeliveryNipuni Maniyamgama0Ki Hyun Bae1Zi Wei Chang2Jialing Lee3Melgious J. Y. Ang4Yong Jie Tan5Lisa F. P. Ng6Laurent Renia7Kevin P. White8Yi Yan Yang9Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR) 20 Biopolis Way, Centros #06‐01 Singapore 138668 Republic of SingaporeBioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR) 20 Biopolis Way, Centros #06‐01 Singapore 138668 Republic of SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Immunos #05‐13 Singapore 138648 Republic of SingaporeBioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR) 20 Biopolis Way, Centros #06‐01 Singapore 138668 Republic of SingaporeBioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR) 20 Biopolis Way, Centros #06‐01 Singapore 138668 Republic of SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Immunos #05‐13 Singapore 138648 Republic of SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Immunos #05‐13 Singapore 138648 Republic of SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs) Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Immunos #05‐13 Singapore 138648 Republic of SingaporeDepartment of Biochemistry and Precision Medicine Translational Research Program Yong Loo Lin School of Medicine National University of Singapore Singapore 119228 Republic of SingaporeBioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR) 20 Biopolis Way, Centros #06‐01 Singapore 138668 Republic of SingaporeAbstract Intranasal delivery of mRNA vaccines offers promising opportunities to combat airborne viruses like SARS‐CoV‐2 by provoking mucosal immunity, which not only defends against respiratory infection but also prevents contagious transmission. However, the development of nasal mRNA vaccines has been hampered by the lack of effective means to overcome the mucus barrier. Herein, ionizable lipid‐incorporated liquid lipid nanoparticles (iLLNs) capable of delivering mRNA cargo across airway mucosa are designed. Adjusting the ratios of ionizable and cationic lipids allows fine‐tuning of the pKa of iLLNs to the range of nasal mucosal pH (5.5–6.5), thus facilitating mucus penetration via the formation of near‐neutral, PEGylated muco‐inert surfaces. When nasally administered to mice, the top candidate iLLN‐2/mRNA complexes enable about 60‐fold greater reporter gene expression in the nasal cavity, compared to the benchmark mRNA‐lipid nanoparticles (ALC‐LNP) having the same lipid composition as that of BNT162b2 vaccine. Moreover, a prime‐boost intranasal immunization of iLLN‐2/mRNA complexes elicits a greater magnitude of SARS‐CoV‐2 spike‐specific mucosal IgA and IgG response than ALC‐LNP, without triggering any noticeable inflammatory reactions. Taken together, these results provide useful insights for the design of nasally deliverable mRNA formulations for prophylactic applications.https://doi.org/10.1002/advs.202407383intranasalionizableliquid lipid nanoparticlesmRNAmuco‐penetrating |
| spellingShingle | Nipuni Maniyamgama Ki Hyun Bae Zi Wei Chang Jialing Lee Melgious J. Y. Ang Yong Jie Tan Lisa F. P. Ng Laurent Renia Kevin P. White Yi Yan Yang Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery Advanced Science intranasal ionizable liquid lipid nanoparticles mRNA muco‐penetrating |
| title | Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery |
| title_full | Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery |
| title_fullStr | Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery |
| title_full_unstemmed | Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery |
| title_short | Muco‐Penetrating Lipid Nanoparticles Having a Liquid Core for Enhanced Intranasal mRNA Delivery |
| title_sort | muco penetrating lipid nanoparticles having a liquid core for enhanced intranasal mrna delivery |
| topic | intranasal ionizable liquid lipid nanoparticles mRNA muco‐penetrating |
| url | https://doi.org/10.1002/advs.202407383 |
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