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For LNPs, polyethylene glycol (PEG) lipids have a crucial role in stabilizing them in aqueous medium, but they severely hinder cellular uptake and reduce transfection efficiency. In this study, we designed ultrasound (US)\u2010assisted fluorinated PEGylated LNPs (F\u2010LNPs) to enhance spleen\u2010targeted mRNA delivery and transfection. Through liquid\u2010to\u2010gas phase transition, we enabled the controlled shedding of fluorinated PEG lipids from F\u2010LNPs, facilitating cellular uptake, membrane fusion, and mRNA release. In vivo results demonstrated that US\u2010assisted F\u2010LNPs increased mRNA transfection approximately 4.0\u2010fold in the spleen following intravenous administration. Notably, the F\u2010LNPs achieved effective mRNA delivery to antigen\u2010presenting cell subsets, such as dendritic cells, macrophages, and B cells. The targeted delivery of full\u2010length ovalbumin\u2010encoding mRNA vaccine induced significant CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell response and exhibited excellent therapeutic effect against the ovalbumin\u2010transduced B16F10 tumor model. These findings establish a novel strategy for spleen\u2010specific mRNA delivery through the combination of fluorinated PEG lipids and US treatment, which holds substantial promise for enhancing the efficacy of immunotherapy, potentially broadening the scope of clinical applications for mRNA\u2010based therapy.\n                  <\/jats:p>","DOI":"10.1002\/anie.202500878","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T06:51:46Z","timestamp":1738133506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Ultrasound\u2010Enhanced Spleen\u2010Targeted mRNA Delivery via Fluorinated PEGylated Lipid Nanoparticles for Immunotherapy"],"prefix":"10.1002","volume":"64","author":[{"given":"Minglong","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of the University of Science and Technology of China State Key Laboratory of 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