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However, most LNPs\u2010based mRNA vaccines usually suffer from insufficient accumulation in APCs due to the lack of active targeting capability, leading to the limited efficacy and the need for high injection dose. In this study, a series of cholesterol\u2010derived mannopolypeptide (CPSM) and cholesterol\u2010conjugated mannose (CM) derivatives is synthesized to prepare mannosylated LNPs for efficient mRNA delivery. The co\u2010assembly of CPSM and\/or CM is demonstrated with ionizable lipid, helper lipid, and cholesterol into LNPs provides the colloidal stability of LNPs, and endows LNPs the ability to target APCs. The leading mannosylated LNPs including CPSM\u2010LNP and CM\/CPSM\u2010LNP exhibit efficient mRNA transfection ability in dendritic cells and mice. Specifically, CPSM\u2010LNP and CM\/CPSM\u2010LNP show preferential accumulation in the lymph nodes compared with commercial ALC\u2010LNP from Pfizer\/BioNTech's COVID\u201019 mRNA vaccine formulation. This study presents a straightforward yet effective strategy to synthesize cholesterol\u2010derived mannopolypeptides and prepare mannosylated LNPs for successful in vivo mRNA delivery.<\/jats:p>","DOI":"10.1002\/smtd.202401712","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:10:53Z","timestamp":1748337053000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Cholesterol\u2010Derived Mannosylated Polypeptide\u2010Formed Lipid Nanoparticles for Efficient in Vivo mRNA Delivery"],"prefix":"10.1002","volume":"9","author":[{"given":"Jin\u2010Yue","family":"Zeng","sequence":"first","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 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Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology Agency for Science, Technology and Research (A*STAR)  Singapore 138673 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology Agency for Science, Technology and Research (A*STAR)  Singapore 138673 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1871-5448","authenticated-orcid":false,"given":"Yi Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Bioprocessing Technology Institute (BTI) Agency for Science, Technology and Research (A*STAR)  20 Biopolis Way, Centros #06\u201001 Singapore 138668 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